This invention relates to novel fused heterocycles which are useful as antagonists of the xcex1vxcex23 and related integrin receptors, to pharmaceutical compositions containing such compounds, processes for preparing such compounds, and to methods of using these compounds, alone or in combination with other therapeutic agents, for the inhibition of cell adhesion and the treatment of angiogenic disorders, inflammation, bone degradation, tumors, metastases, thrombosis, and other cell aggregation-related conditions.
Angiogenesis or neovascularization is critical for normal physiological processes such as embryonic development and wound repair (Folkman and Shing, J. Biol. Chem. 1992, 267:10931-10934; D""Amore and Thompson, Ann. Rev. Physiol. 1987, 49:453-464). However, angiogenesis occurs pathologically, for example, in ocular neovascularization (leading to diabetic retinopathy, neovascular glaucoma, retinal vein occlusion and blindness), in rheumatoid arthritis and in solid tumors (Folkman and Shing, J. Biol. Chem., 1992, 267:10931-10934; Blood and Zetter, Biochim. Biophys. Acta 1990, 1032:118-128).
Tumor dissemination, or metastasis, involves several distinct and complementary components, including the penetration and transversion of tumor cells through basement membranes and the establishment of self-sustaining tumor foci in diverse organ systems. To this end, the development and proliferation of new blood vessels, or angiogenesis, is critical to tumor survival. Without neovascularization, tumor cells lack the nourishment to divide and will not be able to leave the primary tumor site (Folkman and Shing, J. Biol. Chem. 1992, 267:10931-10934).
Inhibition of angiogenesis in animal models of cancer has been shown to result in tumor growth suppression and prevention of metastatic growth (Herblin et al., Exp. Opin. Ther. Patents. 1994, 1-14). Many angiogenic inhibitors have been directed toward blocking initial cytokine-dependent induction of new vessel growth, e.g. antibodies to endothelial cell growth factors. However, these approaches are problematic because tumor and inflammatory cells can secrete multiple activators of angiogenesis (Brooks, et al., Cell 1994, 79:1157-1164). Therefore, a more general approach that would allow inhibition of angiogenesis due to a variety of stimuli would be of benefit.
The integrin xcex1vxcex23 is preferentially expressed on angiogenic blood vessels in chick and man (Brooks, et al., Science 1994, 264:569-571; Enenstein and Kramer, J. Invest. Dermatol. 1994, 103:381-386). Integrin xcex1vxcex23 is the most promiscuous member of the integrin family, allowing endothelial cells to interact with a wide variety of extracellular matrix components (Hynes, Cell 1992, 69:11-25). These adhesive interactions are considered to be critical for angiogenesis since vascular cells must ultimately be capable of invading virtually all tissues.
While integrin xcex1vxcex23 promotes adhesive events important for angiogenesis, this receptor also transmits signals from the extracellular environment to the intracellular compartment (Leavesley, et al., J. Cell Biol. 1993, 121:163-170, 1993). For example, the interaction between the xcex1vxcex23 integrin and extracellular matrix components promotes a calcium signal required for cell motility.
During endothelium injury, the basement membrane zones of blood vessels express several adhesive proteins, including but not limited to von Willebrand factor, fibronectin, and fibrin. Additionally, several members of the integrin family of adhesion receptors are expressed on the surface of endothelial, smooth muscle and on other circulating cells. Among these integrins is xcex1vxcex23, the endothelial cell, fibroblast, and smooth muscle cell receptor for adhesive proteins including von Willebrand factor, fibrinogen (fibrin), vitronectin, thrombospondin, and osteopontin. These integrins initiate a calcium-dependent signaling pathway that can lead to endothelial cell, smooth muscle cell migration and, therefore, may play a fundamental role in vascular cell biology.
An antibody to the xcex1vxcex23 integrin has been developed that inhibits the interaction of this integrin with agonists such as vitronectin (Brooks, et al., Science 1994, 264:569-571). Application of this antibody has been shown to disrupt ongoing angiogenesis on the chick chorioallantoic membrane (CAM), leading to rapid regression of histologically distinct human tumor transplanted onto the CAM (Brooks, et al., Cell 1994, 79:1157-1164). In this model, antagonists of the xcex1vxcex23 integrin induced apoptosis of the proliferating angiogenic vascular cells, leaving pre-existing quiescent blood vessels unaffected. Thus, xcex1vxcex23 integrin antagonists have been shown to inhibit angiogenesis. Based on this property, therapeutic utility of such agents is expected in human diseases such as cancer, rheumatoid arthritis and ocular vasculopathies (Folkman and Shing, J. Biol. Chem. 1992, 267:10931-10934).
Increasing numbers of other cell surface receptors have been identified which bind to extracellular matrix ligands or other cell adhesion ligands thereby mediating cell-cell and cell-matrix adhesion processes. These receptors belong to a gene superfamily called integrins and are composed of heterodimeric transmembrane glycoproteins containing xcex1- and xcex2-subunits. Integrin subfamilies contain a common xcex2-subunit combined with different xcex1-subunits to form adhesion receptors with unique specificity. The genes for eight distinct xcex2-subunits have been cloned and sequenced to date.
Two members of the xcex21 subfamily, xcex14xcex21 and xcex15xcex21 have been implicated in various inflammatory processes. Antibodies to xcex14prevent adhesion of lymphocytes to synovial endothelial cells in vitro, a process which may be of importance in rheumatoid arthritis (VanDinther-Janssen, et al., J. Immunol. 1991, 147:4207). Additional studies with monoclonal anti-xcex14antibodies provide evidence that xcex14xcex21 may additionally have a role in allergy, asthma, and autoimmune disorders (Walsh, et al., J. Immunol. 1991, 146:3419; Bochner, et al., J. Exp. Med. 1991 173:1553; Yednock, et al., Nature 1992, 356:63). Anti-xcex14 antibodies also block the migration of leukocytes to the site of inflammation (Issedutz, et al., J. Immunol. 1991, 147:4178).
The xcex1vxcex23 heterodimer is a member of the xcex23 integrin subfamily and has been identified on platelets, endothelial cells, melanoma, smooth muscle cells, and osteoclasts (Horton and Davies, J. Bone Min. Res. 1989, 4:803-808; Davies, et al., J. Cell. Biol. 1989, 109:1817-1826; Horton, Int. J. Exp. Pathol. 1990, 71:741-759). Like GPIIb/IIIa, the vitronectin receptor binds a variety of RGD-containing adhesive proteins such as vitronectin, fibronectin, VWF, fibrinogen, osteopontin, bone sialo protein II and thrombospondin in a manner mediated by the RGD sequence. A key event in bone resorption is the adhesion of osteoclasts to the matrix of bone. Studies with monoclonal antibodies have implicated the xcex1vxcex23 receptor in this process and suggest that a selective xcex1vxcex23 antagonist would have utility in blocking bone resorption (Horton, et al., J. Bone Miner. Res. 1993, 8:239-247; Helfrich, et al., J. Bone Miner. Res. 1992, 7:335-343).
PCT Patent Application WO 94/22835 discloses compounds having the general formula:
(M1)nxe2x80x94Qxe2x80x94(M2)1xe2x88x92nxe2x80x94Lxe2x80x94A
European Patent Application Publication Number 614664 discloses compounds having the general formula: 
PCT Patent Application WO 94/29273 discloses compounds having the general formula: 
R, R*=carboxy bearing alkyl group
R6=amine bearing group
PCT Patent Application WO 96/18602 discloses compounds having the general formula: 
European Patent Application Publication Number EP 635492 discloses compounds having the general formula: 
PCT Patent Application WO 96/22288 discloses compounds having the general formula: 
None of the above references teaches or suggests the compounds of the present invention which are described in detail below.
The present invention provides novel compounds which bind to integrin receptors thereby altering cell-matrix and cell-cell adhesion processes. The compounds of the present invention are useful for the treatment of angiogenic disorders, inflammation, bone degradation, tumors, metastases, thrombosis, and other cell aggregation-related conditions in a mammal.
One aspect of this invention provides novel compounds of Formulae I-IV (described below) which are useful as antagonists of the xcex1vxcex23 receptor. The compounds of this invention inhibit the binding of vitronectin to xcex1vxcex23 and inhibit cell adhesion. This invention also includes pharmaceutical compositions containing such compounds of Formulae I-IV, and methods of their use for the inhibition of angiogenesis, and/or for the treatment of angiogenic disorders.
The present invention also provides novel compounds, pharmaceutical compositions and methods which may be used in the treatment or prevention of diseases which involve cell adhesion processes, including, but not limited to, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, metastasis, wound healing, diabetic retinopathy, ocular vasculopathies, thrombosis, inflammatory bowel disease and other autoimmune diseases.
Also included in this invention are pharmaceutical kits containing dosage units of a compound of Formulae I-IV, for the treatment of cell adhesion related disorders, including, but not limited to, angiogenic disorders.
The present invention provides novel compounds of Formulae I-IV (described below) which bind to integrin receptors thereby altering cell-matrix and cell-cell adhesion processes. The compounds of this invention are useful for the treatment of angiogenic disorders, inflammation, bone degradation, tumors, metastases, thrombosis, and other cell aggregation-related conditions in a mammal.
One aspect of this invention provides novel compounds of Formulae I-IV (described below) which are useful as antagonists of the xcex1vxcex23 receptor. The compounds of this invention inhibit the binding of vitronectin to xcex1vxcex23 and inhibit cell adhesion. This invention also includes pharmaceutical compositions containing such compounds of Formulae I-IV, and methods of using such compounds for the inhibition of angiogenesis, and/or for the treatment of angiogenic disorders.
[1a] In a first embodiment the present invention comprises compounds of Formula I: 
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
R1 is selected from: 
D is xe2x80x94N(R12)xe2x80x94 or xe2x80x94Sxe2x80x94;
J is xe2x80x94C(R2)xe2x80x94 or xe2x80x94Nxe2x80x94;
K, L and M are independently xe2x80x94C(R2)xe2x80x94 or xe2x80x94C(R3)xe2x80x94;
R2 and R3 are independently selected from:
H, C1-C4 alkoxy, NR11R12, halogen, NO2, CN, CF3, C1-C6 alkyl, C3-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl), aryl(C1-C6 akyl)-, (C1-C6 alkyl)carbonyl, (C1-C6 alkoxy)carbonyl, arylcarbonyl, and aryl substituted with 0-4 R7,
alternatively, when R2 and R3 are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3 and NO2;
R2a is selected from:
H, C1-C10 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl), aryl, aryl(C1-C4 alkyl)-, (C2-C7 alkyl)carbonyl, arylcarbonyl, (C2-C10 alkoxy)carbonyl, C3-C7 cycloalkoxycarbonyl, C7-C11 bicycloalkoxycarbonyl, aryloxycarbonyl, aryl(C1-C10 alkoxy)carbonyl, C1-C6 alkylcarbonyloxy(C1-C4 alkoxy)carbonyl, arylcarbonyloxy(C1-C4 alkoxy)carbonyl, and C3-C7 cycloalkylcarbonyloxy(C1-C4 alkoxy)carbonyl;
R4 is selected from:
H, C1-C10 alkyl, (C1-C10 alkyl)carbonyl, aryl, aryl(C1-C4 alkyl)-, C3-C11cycloalkyl, and C3-C11 cycloalkyl(C1-C4 alkyl)-;
U is selected from:
xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nO(CH2)mxe2x80x94, xe2x80x94(CH2)nN(R12) (CH2)mxe2x80x94, xe2x80x94N(H)(CH2)nxe2x80x94, xe2x80x94(CH2)nC(xe2x95x90O)(CH2)mxe2x80x94, xe2x80x94(CH2)nS(O)p(CH2)mxe2x80x94, xe2x80x94(CH2)nNHNH(CH2)mxe2x80x94, xe2x80x94N(R10)C(xe2x95x90O)xe2x80x94, xe2x80x94NHC(xe2x95x90O)(CH2)nxe2x80x94, xe2x80x94C(xe2x95x90O)N(R10)xe2x80x94, and xe2x80x94N(R10)S(O)pxe2x80x94;
W is xe2x80x94C(xe2x95x90O)xe2x80x94N(R10)xe2x80x94(C1-C3 alkylene)-, in which the alkylene group is substituted by R8 and by R9:
R8 and R9 are independently selected from:
H, CO2R18b, C(xe2x95x90O)R18b, CONR17R18b 
hydroxy, C5-C10 alkoxy, nitro, xe2x80x94N(R10)R11, xe2x80x94N(R16)R17, aryl(C0-C6 alkyl)carbonyl, aryl(C3-C6 alkyl), heteroaryl(C1-C6 alkyl), CONR18aR20, SO2R18a, SO2NR18aR20,
C1-C10 alkyl substituted with 0-1 R6,
C5-C10 alkenyl substituted with 0-1 R6,
C5-C10 alkynyl substituted with 0-1 R6,
C3-C8 cycloalkyl substituted with 0-1 R6,
C5-C6 cycloalkenyl substituted with 0-1 R6,
C1-C10 alkylcarbonyl,
C3-C10 cycloalkyl(C1-C4 alkyl)-, phenyl substituted with 1-3 R6,
naphthyl substituted with 0-3 R6,
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7, and
C5-C10 alkyl substituted with 0-3 R7,
providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R7;
R6 is selected from:
H, C1-C10 alkyl, hydroxy, C1-C10 alkoxy, nitro, C1-C10 alkylcarbonyl, xe2x80x94N(R11)R12, cyano, halo, CF3, CHO, CO2R18b, C(xe2x95x90O)R18b, CONR17R18b, OC(xe2x95x90O)R10, OR10, OC(xe2x95x90O)NR10R11, NR10C(xe2x95x90O)R10, NR10C(xe2x95x90O)OR21, NR10C(xe2x95x90O)NR10R11, NR10SO2NR10R11, NR10SO2R21, S(O)pR11, SO2NR10R11,
aryl substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(O)mMe, and xe2x80x94NMe2,
aryl(C1-C4 alkyl)-, said aryl being substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(O)pMe, and xe2x80x94NMe2, and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7;
R7 is selected from:
H, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl(C1-C4 alkyl)-, (C1-C4 alkyl)carbonyl, CO2R18a, SO2R11, SO2NR10R11, OR10, and N(R11)R12;
R10 is selected from:
H, C3-C6 alkenyl, C3-C11 cycloalkyl, aryl, (C3-C11cycloalkyl)methyl, aryl(C1-C4 alkyl), and C1-C10 alkyl substituted with 0-2 R6;
R11 is selected from:
H, hydroxy, C1-C8 alkyl, C3-C6 alkenyl, C3-C11 cycloalkyl, (C3-C11 cycloalkyl)methyl, C1-C6 alkoxy,
benzyloxy, aryl, heteroaryl, heteroaryl(C1-C4 alkyl)-,
aryl(C1-C4 alkyl), adamantylmethyl, and
C1-C10 alkyl substituted with 0-2 R4,
alternatively, when R10 and R11 are both substituents on the same nitrogen atom (as in xe2x80x94NR10R11) they may be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from:
3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;
said heterocycle being substituted with 0-3 groups selected from: C1-C6 alkyl, aryl, heteroaryl, aryl(C1-C4 alkyl)-, (C1-C6 alkyl)carbonyl, (C3-C7 cycloalkyl)carbonyl, (C1-C6 alkoxy)carbonyl, aryl(C1-C4 alkoxy)carbonyl, C1-C6 alkylsulfonyl, and arylsulfonyl;
R12 is selected from:
H, C1-C6 alkyl, triphenylmethyl, methoxymethyl, methoxyphenyldiphenylmethyl,
trimethylsilylethoxymethyl, (C1-C6 alkyl)carbonyl,
(C1-C6 alkoxy)carbonyl, (C1-C6 alkyl)aminocarbonyl,
C3-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, heteroaryl(C1-C6 alkyl)carbonyl,
heteroarylcarbonyl, aryl(C1-C6 alkyl)-,
(C1-C6 alkyl)carbonyl, arylcarbonyl, C1-C6 
alkylsulfonyl, arylsulfonyl, aryl(C1-C6 alkyl)sulfonyl,
heteroarylsulfonyl, heteroaryl(C1-C6 alkyl)sulfonyl,
aryloxycarbonyl, and aryl(C1-C6 alkoxy)carbonyl,
wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and nitro;
R14 is selected from H, C1-C4 alkyl, and phenyl(C1-C4 alkyl);
R16 is selected from:
xe2x80x94C(xe2x95x90O)OR18a, xe2x80x94C(xe2x95x90O)R18b, xe2x80x94C(xe2x95x90O)N(R18b)2, xe2x80x94C(xe2x95x90O)NHSO2R18a,
xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)R18b, xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)OR18a,
xe2x80x94C(xe2x95x90O)NHSO2NHR18b, xe2x80x94SO2R18a, xe2x80x94SO2N(R18b)2, and
xe2x80x94SO2NHC(xe2x95x90O)OR18b;
R17 is selected from:
H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, aryl(C1-C6 alkyl)-, and heteroaryl(C1-C6 alkyl);
R18a is selected from:
C7-C8 alkyl, C3-C11 cycloalkyl,
aryl(C1-C6 alkyl)-, said aryl substituted with 0-4 R19,
heteroaryl(C1-C6 alkyl)-, said heteroaryl substituted with 0-4 R19,
(C1-C6 alkyl)heteroaryl, said heteroaryl substituted with 0-4 R19,
heteroaryl substituted with 0-4 R19,
phenyl substituted with 3-4 R19, and
naphthyl substituted with 0-4 R19;
R18b is H or R18a;
R19 is selected from:
H, halogen, CF3, CO2H, CN, N2, xe2x80x94NR11R12, OCF3,
C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
C3-C11 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-,
aryl(C1-C6 alkyl)-, C1-C6 alkoxy, C1-C4 alkoxycarbonyl,
aryl, aryl-Oxe2x80x94, aryl-SO2xe2x80x94, heteroaryl, and
heteroaryl-SO2xe2x80x94, wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF3, C1-C3 alkyl, and C1-C3 alkoxy;
R20 is selected from:
hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy,
aryloxy, aryl(C1-C4 alkyl)oxy,
C2-C10 alkylcarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyloxy (C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyl (C1-C2 alkyl)oxy-,
C3-C10 cycloalkylcarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10 cycloalkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10 cycloalkoxycarbonyl (C1-C2 alkyl)oxy-,
aryloxycarbonyl(C1-C2 alkyl)oxy-,
aryloxycarbonyloxy(C1-C2 alkyl)oxy-,
arylcarbonyloxy(C1-C2 alkyl)oxy-,
C1-C5 alkoxy(C1-C5 alkyl)carbonyloxy(C1-C2 alkyl)oxy-,
(5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and
(R10)(R11)Nxe2x80x94(C1-C10 alkoxy)-;
R21 is selected from:
C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, (C3-C11 cycloalkyl)methyl, aryl, aryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 0-2 R7;
Y is selected from:
xe2x80x94COR20, xe2x80x94SO3H, xe2x80x94PO3H, xe2x80x94CONHNHSO2CF3, xe2x80x94CONHSO2R18a,
xe2x80x94CONHSO2NHR18b, xe2x80x94NHCOCF3, xe2x80x94NHCONHSO2R18a, xe2x80x94NHSO2R18a,
xe2x80x94OPO3H2, xe2x80x94OSO3H, xe2x80x94PO3H2, xe2x80x94SO3H,
xe2x80x94SO2NHCOR18a, xe2x80x94SO2NHCO2R18a, 
m is 0-2;
n is 0-4;
p is 0-2;
with the following provisos:
(1) n and m are chosen such that the number of atoms connecting R1 and Y is in the range of 8-14;
(2) in W, the alkylene group is substituted with at least one R8 or R9 which is not H;
(3) in the definition of W, when there is only one non-hydrogen substituent on the alkylene group, such substituent may not be an unsubstituted pyridyl radical.
[1b] A preferred embodiment of the present invention are compounds of Formula III: 
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
R1 is selected from: 
U is selected from xe2x80x94(CH2)nxe2x80x94, (CH2)nO(CH2)mxe2x80x94, xe2x80x94NH(CH2)nxe2x80x94, xe2x80x94(CH2)nC(xe2x95x90O)(CH2)mxe2x80x94, xe2x80x94N(R10)C(xe2x95x90O)xe2x80x94, and xe2x80x94NHC(xe2x95x90O)(CH2)nxe2x80x94;
R2 and R3 are independently selected from:
H, C1-C4 alkoxy, NR11R12, halogen, NO2, CN, CF3, C1-C6 alkyl, C3-C6 alkenyl, C3-C7 cycloalkyl,
C3-C7 cycloalkyl(C1-C4 alkyl), aryl(C1-C6 alkyl)-,
(C1-C6 alkyl)carbonyl, (C1-C6 alkoxy)carbonyl,
arylcarbonyl, and aryl substituted with 0-4 R7,
alternatively, when R2 and R3 are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3 and NO2;
R4 is selected from:
H, C1-C10 alkyl, (C1-C10 alkyl)carbonyl, aryl,
aryl(C1-C4 alkyl)-, C3-C11 cycloalkyl, and
C3-C11 cycloalkyl(C1-C4 alkyl)-;
R8 is selected from:
H, CO2R18b, C(xe2x95x90O)R18b, CONR17R18b,
C1-C1 alkyl substituted with 0-1 R6,
C5-C10 alkenyl substituted with 0-1 R6,
C5-C10 alkynyl substituted with 0-1 R6,
C3-C8 cycloalkyl substituted with 0-1 R6,
C5-C6 cycloalkenyl substituted with 0-1 R6,
C1-C10 alkylcarbonyl,
C3-C10 cycloalkyl(C1-C4 alkyl)-,
phenyl substituted with 1-3 R6,
naphthyl substituted with 0-3 R6,
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7;
R9 is selected from:
H, hydroxy, C5-C10 alkoxy, nitro, N(R10)R11, N(R16)R17, aryl(C0-C6 alkyl)carbonyl, aryl(C3-C6 alkyl), heteroaryl(C1-C6 alkyl), CONR18aR20), SO2R18a, SO2NR18aR20),
C1-C10 alkyl substituted with 0-1 R6,
C5-C10 alkenyl substituted with 0-1 R6,
C5-C10 alkynyl substituted with 0-1 R6,
C3-C8 cycloalkyl substituted with 0-1 R6,
C5-C6 cycloalkenyl substituted with 0-1 R6,
C1-C10 alkylcarbonyl, C3-C10 cycloalkyl(C1-C4 alkyl),
phenyl substituted with 1-3 R6,
naphthyl substituted with 0-3 R6, and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7,
providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R7;
R6 is selected from:
H, C1-C10 alkyl, hydroxy, C1-C10 alkoxy, nitro, C1-C10 alkylcarbonyl, xe2x80x94N(R11)R12, cyano, halo, CF3, CHO, CO2R18b, C(xe2x95x90O)R18b, CONR17R18b, OC(xe2x95x90O)R10, OR10, OC(xe2x95x90O)NR10R11, NR10C(xe2x95x90O)R10, NR10C(xe2x95x90O)OR21, NR10C(xe2x95x90O)NR10R11, NR10SO2NR10R11, NR10SO2R21, S(O)pR11, SO2NR10R11,
aryl substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(O)mMe, and xe2x80x94NMe2,
aryl(C1-C4 alkyl)-, said aryl being substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(O)pMe, and xe2x80x94NMe2, and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7;
R7 is selected from:
H, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl(C1-C4 alkyl)-, (C1-C4 alkyl)carbonyl, CO2R18a, SO2R11,
SO2NR10R11, OR10, and N(R11)R12;
R10 is selected from:
H, C3-C6 alkenyl, C3-C11 cycloalkyl, aryl,
(C3-C11 cycloalkyl)methyl, aryl(C1-C4 alkyl), and C1-C10 alkyl substituted with 0-2 R6;
R11 is selected from:
H, hydroxy, C1-C8 alkyl, C3-C6 alkenyl, C3-C11 cycloalkyl, (C3-C11 cycloalkyl)methyl, C1-C6 alkoxy, benzyloxy, aryl, heteroaryl, heteroaryl(C1-C4 alkyl)-, aryl(C1-C4 alkyl), adamantylmethyl, and C1-C10 alkyl substituted with 0-2 R4,
alternatively, when R10 and R11 are both substituents on the same nitrogen atom (as in xe2x80x94NR10OR11) they may be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from:
3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;
said heterocycle being substituted with 0-3 groups selected from: C1-C6 alkyl, aryl, heteroaryl, aryl(C1-C4 alkyl)-, (C1-C6 alkyl)carbonyl, (C3-C7 cycloalkyl)carbonyl, (C1-C6 alkoxy)carbonyl, aryl(C1-C4 alkoxy)carbonyl, C1-C6 alkylsulfonyl, and arylsulfonyl;
R12 is selected from:
H, C1-C6 alkyl, triphenylmethyl, methoxymethyl, methoxyphenyldiphenylmethyl,
trimethylsilylethoxymethyl, (C1-C6 alkyl)carbonyl,
(C1-C6 alkoxy)carbonyl, (C1-C6 alkyl)aminocarbonyl,
C3-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, heteroaryl(C1-C6 alkyl)carbonyl,
heteroarylcarbonyl, aryl(C1-C6 alkyl)-,
(C1-C6 alkyl)carbonyl, arylcarbonyl, C1-C6 alkylsulfonyl, arylsulfonyl, aryl(C1-C6 alkyl)sulfonyl,
heteroarylsulfonyl, heteroaryl(C1-C6 alkyl)sulfonyl,
aryloxycarbonyl, and aryl(C1-C6 alkoxy)carbonyl,
wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and nitro;
R14 is selected from H, C1-C4 alkyl, and phenyl(C1-C4 alkyl);
R16 is selected from xe2x80x94C(xe2x95x90O)OR18a, xe2x80x94C(xe2x95x90O)R18b, xe2x80x94C(xe2x95x90O)N(R18b)2, xe2x80x94SO2R18a, and xe2x80x94SO2N(R18b)2;
R17 is selected from:
H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, aryl(C1-C6 alkyl)-, and heteroaryl(C1-C6 alkyl);
R18a is selected from:
C7-C8 alkyl, C3-C11 cycloalkyl,
aryl(C1-C6 alkyl)-, said aryl substituted with 0-4 R19,
heteroaryl(C1-C6 alkyl)-, said heteroaryl substituted with 0-4 R19,
(C1-C6 alkyl)heteroaryl, said heteroaryl substituted with 0-4 R19,
heteroaryl substituted with 0-4 R19,
phenyl substituted with 3-4 R19, and
naphthyl substituted with 0-4 R19;
R18b is H or R18a;
R19 is selected from:
H, halogen, CF3, CO2H, CN, NO2, xe2x80x94NR11R12, OCF3,
C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
C3-C11 cycloalkyl, C3-C7 cycloalkyl (C1-C4 alkyl)-,
aryl(C1-C6 alkyl)-, C1-C6 alkoxy, C1-C4 alkoxycarbonyl,
aryl, aryl-Oxe2x80x94, aryl-SO2xe2x80x94, heteroaryl, and
heteroaryl-SO2xe2x80x94, wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF3, C1-C3 alkyl, and C1-C3 alkoxy;
R20 is selected from:
hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy,
aryloxy, aryl(C1-C4 alkyl)oxy,
C2-C10 alkylcarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyl(C1-C2 alkyl)oxy-,
C3-C10 cycloalkylcarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10 cycloalkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10 cycloalkoxycarbonyl(C1-C2 alkyl)oxy-,
aryloxycarbonyl(C1-C2 alkyl)oxy-,
aryloxycarbonyloxy(C1-C2 alkyl)oxy-,
arylcarbonyloxy(C1-C2 alkyl)oxy-,
C1-C5 alkoxy(C1-C5 alkyl)carbonyloxy(C1-C2 alkyl)oxy-,
(5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and
(R10)(R11)Nxe2x80x94(C1-C10 alkoxy)-;
R21 is selected from:
C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, (C3-C11 cycloalkyl)methyl, aryl, aryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 0-2 R7;
m is 0-2;
n is 0-3; and
p is 0-2;
with the following provisos:
(1) n and m are chosen such that the number of atoms connecting R1 and xe2x80x94COR20 in Formula (III) is in the range of 8-14,
(2) if R8 is H, then R9 may not be an unsubstituted pyridyl radical,
(3) if R9 is H, then R8 may not be an unsubstituted pyridyl radical.
[1c] A more preferred embodiment of the present invention are compounds of Formula III: 
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
R1 is selected from: 
[1d] An even more preferred embodiment of the present invention are compounds of Formula III: 
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
R1 is selected from: 
U is selected from xe2x80x94(CH2)nxe2x80x94, xe2x80x94NH(CH2)nxe2x80x94, xe2x80x94N(R10)C(xe2x95x90O)xe2x80x94, and xe2x80x94NHC(xe2x95x90O)(CH2)nxe2x80x94;
R4 is selected from:
H, C1-C4 alkyl, (C1-C4 alkyl)carbonyl, aryl,
aryl(C1-C4 alkyl)-, C3-C6 cycloalkyl, and
C3-C6 cycloalkyl(C1-C4 alkyl)-;
R6 is H;
R7 is selected from:
H, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl(Cl-C4 alkyl)-, (C1-C4 alkyl)carbonyl, CO2R18a, SO2R11, SO2NR10R11, OR10, and N(R11)R12;
R8 is H;
R9 is selected from:
H, hydroxy, C5-C10 alkoxy, nitro, N(R10)R11, N(R16)R17, aryl(C0-C6 alkyl)carbonyl, aryl(C3-C6 alkyl), heteroaryl(C1-C6 alkyl), CONR18aR20, SO2R18a, SO2NR18aR20,
providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R7;
R10 is selected from:
H, C3-C6 alkenyl, C3-C6 cycloalkyl, aryl, (C3-C6 cycloalkyl)methyl, aryl(C1-C4 alkyl), and C1-C4 alkyl;
R11 is selected from:
H, hydroxy, C1-C4 alkyl, C3-C6 alkenyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)methyl, C1-C6 alkoxy, benzyloxy, aryl, heteroaryl, heteroaryl(C1-C4 alkyl)-, aryl(C1-C4 alkyl), adamantylmethyl, and C1-C4 alkyl substituted with 0-2 R4,
R12 is selected from:
H, C1-C4 alkyl, (C1-C4 alkyl)carbonyl, (C1-C4 alkoxy)carbonyl, phenyl(C1-C4 alkyl)-, phenylsulfonyl,
phenyloxycarbonyl, and phenyl(C1-C4 alkoxy)carbonyl,
wherein said phenyl groups are substituted with 0-2 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and nitro;
R14 is selected from H, methyl, ethyl, benzyl and phenylethyl;
R16 is selected from xe2x80x94C(xe2x95x90O)OR18a, xe2x80x94C(xe2x95x90O)R18b, xe2x80x94C(xe2x95x90O)N(R18b)2, xe2x80x94SO2R18a, and xe2x80x94SO2N(R18b)2;
R17 is selected from:
H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, aryl(C1-C6 alkyl)-, and heteroaryl(C1-C6 alkyl);
R18a is selected from:
C7-C8 alkyl, C3-C11 cycloalkyl,
aryl(C1-C6 alkyl)-, said aryl substituted with 0-4 R19,
heteroaryl(C1-C6 alkyl)-, said heteroaryl substituted with 0-4 R19,
(C1-C6 alkyl)heteroaryl, said heteroaryl substituted with 0-4 R19,
heteroaryl substituted with 0-4 R19,
phenyl substituted with 3-4 R19, and
naphthyl substituted with 0-4 R19;
R18b is H or R18a;
R19 is selected from:
H, halogen, CF3, CO2H, CN, NO2, xe2x80x94NR11R12, OCF3,
C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
C3-C11 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-,
aryl(C1-C6 alkyl)-, C1-C6 alkoxy, C1-C4 alkoxycarbonyl,
aryl, aryl-Oxe2x80x94, aryl-SO2xe2x80x94, heteroaryl, and
heteroaryl-SO2xe2x80x94, wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF3, C1-C3 alkyl, and C1-C3 alkoxy;
R20 is selected from:
hydroxy C1-C10 alkyloxy, C3-C11 cycloalkyloxy,
aryloxy, aryl(C1-C4 alkyl)oxy,
C2-C10 alkylcarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyl(C1-C2 alkyl)oxy-,
C3-C10 cycloalkylcarbonyloxy(C1-C2 alkyl)oxy- ,
C3-C10 cycloalkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10 cycloalkoxycarbonyl(C1-C2 alkyl)oxy-,
aryloxycarbonyl (C1-C2 alkyl)oxy-,
aryloxycarbonyloxy(C1-C2 alkyl)oxy-,
arylcarbonyloxy(C1-C2 alkyl)oxy-,
C1-C5 alkoxy(C1-C5 alkyl)carbonyloxy(C1-C2 alkyl)oxy-,
(5(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and
(R10)(R11)Nxe2x80x94(C1-C10 alkoxy)-;
R21 is selected from:
C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, (C3-C11 cycloalkyl)methyl, aryl, aryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 0-2 R7;
m is 0-2;
n is 0-3; and
p is 0-2;
with the following provisos:
(1) n and m are chosen such that the number of atoms connecting R1 and xe2x80x94COR20 in Formula (III) is in the range of 8-14,
(2) if R8 is H, then R9 may not be an unsubstituted pyridyl radical,
(3) if R9 is H, then may not be an unsubstituted pyridyl radical.
[1e] Specifically preferred compounds of Formula III including enantiomeric or diastereomeric forms thereof, or mixtures of enantiomeric or diastereomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof selected from the group consisting of:
3-[7-[(imidazol-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-(3,5-dimethylisoxazol-4-ylsulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(pyridin-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-((4-phenylbenzene)sulfonylamino)propionic acid,
3-[7-[(benzimidazol-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4-methylimidazol-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4,5-dimethylimidazol-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4,5,6,7-tetrahydrobenzimidazol-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-(2-aminopyridin-6-yl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(7-azabenzimidazol-2-yl)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(benzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(pyridin-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(pyridin-2-ylamino)methyl]-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbon-ylamino]-2-((4-phenylbenzene)sulfonylamino)propionic acid,
3-[7-[(benzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4-methylimidazol-2-ylamino)methyl]-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4,5-dimethylimidazol-2-ylamino)methyl]-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4,5,6,7-tetrahydrobenzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-(2-aminopyridin-6-yl)1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(7-azabenzimidazol-2-yl)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbon-ylamino]-2-((2,2-dimethyl-4-phenylbenzene)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbon-ylamino]-2-((2,2-dichloro-4-phenylbenzene)sulfonylamino)propionic acid.
[2a] In a second embodiment of the present invention are compounds of Formula II: 
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
R1 is selected from: 
A is xe2x80x94CH2xe2x80x94 or xe2x80x94N(R12)xe2x80x94;
A1 and B are independently xe2x80x94CH2xe2x80x94 or xe2x80x94N(R10)xe2x80x94;
D is xe2x80x94N(R12)xe2x80x94 or xe2x80x94Sxe2x80x94;
Exe2x80x94F is xe2x80x94C(R2)xe2x95x90C(R3)xe2x80x94 or xe2x80x94C(R2)2C(R3)2xe2x80x94;
J is xe2x80x94C(R2)xe2x80x94 or xe2x80x94Nxe2x80x94;
K, L and M are independently xe2x80x94C(R2)xe2x80x94 or xe2x80x94C(R3)xe2x80x94;
R2 and R3 are independently selected from:
H, C1-C4 alkoxy, NR11R12, halogen, N2, CN, CF3, C1-C6 alkyl, C3-C6 alkenyl, C3-C7 cycloalkyl,
C3-C7 cycloalkyl(C1-C4 alkyl), aryl(C1-C6 alkyl)-,
(C1-C6 alkyl)carbonyl, (C1-C6 alkoxy)carbonyl,
arylcarbonyl, and aryl substituted with 0-4 R7,
alternatively, when R2 and R3 are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3 and NO2;
R2a is selected from:
H, C1-C10 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl,
C3-C7 cycloalkyl(C1-C4 alkyl), aryl, aryl(C1-C4 alkyl)-, (C2-C7 alkyl)carbonyl, arylcarbonyl,
(C2-C10 alkoxy)carbonyl, C3-C7 cycloalkoxycarbonyl,
C7-C11 bicycloalkoxycarbonyl, aryloxycarbonyl,
aryl(C1-C10 alkoxy)carbonyl,
C1-C6 alkylcarbonyloxy(C1-C4 alkoxy)carbonyl,
arylcarbonyloxy(C1-C4 alkoxy)carbonyl, and
C3-C7 cycloalkylcarbonyloxy(C1-C4 alkoxy)carbonyl;
R4 is selected from:
H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl (C1-C4 alkyl)-, (C1-C10 alkyl)carbonyl, aryl, heteroaryl,
aryl(C1-C6 alkyl)-, and heteroaryl(C1-C6 alkyl)-,
wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2,
R6 is selected from:
H, C1-C10 alkyl, hydroxy, C1-C10 alkoxy, nitro, C1-C10 alkylcarbonyl, xe2x80x94N(R11)R12, cyano, halo, CF3, CHO, CO2R18b, C(xe2x95x90O)R18b, CONR17R18b, OC(xe2x95x90O)R10, OR10, OC(xe2x95x90O)NR10R11, NR10C(xe2x95x90O)R10, NR10C(xe2x95x90O)OR21, NR10C(xe2x95x90O)NR10R11, NR10SO2NR10R11, NR10SO2R21, S(O)pR11, SO2NR10R11,
aryl substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(O)mMe, and xe2x80x94NMe2,
aryl(C1-C4 alkyl)-, said aryl being substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(O)pMe, and xe2x80x94NMe2, and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7;
R7 is selected from:
H, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl(C1-C4 alkyl)-, (C1-C4 alkyl)carbonyl, CO2R18a, S2R11,
SO2NR10R11, OR10, and N(R11)R12;
U is selected from:
xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nO(CH2)mxe2x80x94, xe2x80x94(CH2)nN(R12)(CH2)mxe2x80x94,
xe2x80x94NH(CH2)nxe2x80x94, xe2x80x94(CH2)nC(xe2x95x90O)(CH2)mxe2x80x94, xe2x80x94(CH2)nS(O)p(CH2)mxe2x80x94,
xe2x80x94(CH2)nNNHNH(CH2)mxe2x80x94, xe2x80x94N(R10)C(xe2x95x90O)xe2x80x94, xe2x80x94NHC(xe2x95x90O)(CH2)nxe2x80x94,
xe2x80x94C(xe2x95x90O)N(R10)xe2x80x94, and xe2x80x94N(R10)S(O)pxe2x80x94;
G is N or CR19;
W is xe2x80x94C(xe2x95x90O)xe2x80x94N(R10)xe2x80x94(C1-C3 alkylene)-, in which the alkylene group is substituted by R8 and by R9:
R8 and R9 are independently selected from:
H, CO2R18b, C(xe2x95x90O)R18b, CONR17R18b,
C1-C10 alkyl substituted with 0-1 R6,
C2-C10 alkenyl substituted with 0-1 R6,
C2-C10 alkynyl substituted with 0-1 R6,
C3-C8 cycloalkyl substituted with 0-1 R6,
C5-C6 cycloalkenyl substituted with 0-1 R6,
(C1-C10 alkyl)carbonyl,
C3-C10 cycloalkyl(C1-C4 alkyl)-,
phenyl substituted with 0-3 R6,
naphthyl substituted with 0-3 R6,
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7,
C1-C10 alkoxy substituted with 0-2 R7,
hydroxy, nitro, xe2x80x94N(R10)R11, xe2x80x94N(R16)R17, aryl(C0-C6 alkyl)carbonyl, aryl(C3-C6 alkyl), heteroaryl(C1-C6 alkyl), CONR18aR20), SO2R18a, and SO2NR18aR20,
providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R7;
R10 is selected from:
H, CF3, C3-C6 alkenyl, C3-C11 cycloalkyl, aryl,
(C3-C11 cycloalkyl)methyl, aryl(C1-C4 alkyl), and C1-C10 alkyl substituted with 0-2 R6;
R11 is selected from:
H, hydroxy, C1-C8 alkyl, C3-C6 alkenyl, C3-C11 cycloalkyl, (C3-C11 cycloalkyl)methyl, C1-C6 alkoxy,
benzyloxy, aryl, heteroaryl, heteroaryl(C1-C4 alkyl)-,
aryl(C1-C4 alkyl), adamantylmethyl, and
C1-C10 alkyl substituted with 0-2 R4;
alternatively, when R10 and R11 are both substituents on the same nitrogen atom (as in xe2x80x94NR10R11) they may be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from:
3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;
said heterocycle being substituted with 0-3 groups selected from: C1-C6 alkyl, aryl, heteroaryl, aryl(C1-C4 alkyl)-, (C1-C6 alkyl)carbonyl, (C3-C7 cycloalkyl)carbonyl, (C1-C6 alkoxy)carbonyl, aryl(C1-C4 alkoxy)carbonyl, C1-C6 alkylsulfonyl, and arylsulfonyl;
R12 is selected from:
H, C1-C6 alkyl, triphenylmethyl, methoxymethyl,
methoxyphenyldiphenylmethyl,
trimethylsilylethoxymethyl, (C1-C6 alkyl)carbonyl,
(C1-C6 alkoxy)carbonyl, (C1-C6 alkyl)aminocarbonyl,
C3-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, heteroaryl(C1-C6 alkyl)carbonyl,
heteroarylcarbonyl, aryl(C1-C6 alkyl)-,
(C1-C6 alkyl)carbonyl, arylcarbonyl, C1-C6 
alkylsulfonyl, arylsulfonyl, aryl(C1-C6 alkyl)sulfonyl,
heteroarylsulfonyl, heteroaryl(C1-C6 alkyl)sulfonyl,
aryloxycarbonyl, and aryl(C1-C6 alkoxy)carbonyl,
wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and nitro;
R16 is selected from:
xe2x80x94C(xe2x95x90O)OR18a, xe2x80x94C(xe2x95x90O)R18b, xe2x80x94C(xe2x95x90O)N(R18b)2, xe2x80x94C(xe2x95x90O)NHSO2R18a,
xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)R18b, xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)OR18a,
xe2x80x94C(xe2x95x90O)NHS2NHR18b, xe2x80x94SO2R18a, xe2x80x94SO2N(R18b)2, and
xe2x80x94SO2NHC(xe2x95x90O)OR18b;
R17 is selected from:
H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, aryl(C1-C6 alkyl)-, and heteroaryl(C1-C6 alkyl);
R18a is selected from:
C1-C8 alkyl, C3-C11 cycloalkyl,
aryl(C1-C6 alkyl)-, said aryl substituted with 0-4 R19,
heteroaryl(C1-C6 alkyl)-, said heteroaryl substituted with 0-4 R19,
(C1-C6 alkyl)heteroaryl, said heteroaryl substituted with 0-4 R19,
heteroaryl substituted with 0-4 R19 
phenyl substituted with 0-4 R19, and
naphthyl substituted with 0-4 R19;
R18bis H or R18a;
R19 is selected from:
H, halogen, CF3, CO2H, CN, N2, xe2x80x94NR11R12, OCF3,
C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
C3-C11 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-,
aryl(C1-C6 alkyl)-, C1-C6 alkoxy, C1-C4 alkoxycarbonyl,
aryl, aryl-Oxe2x80x94, aryl-SO2xe2x80x94, heteroaryl, and
heteroaryl-SO2xe2x80x94, wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF3, C1-C3 alkyl, and C1-C3 alkoxy;
R20 is selected from:
hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy,
aryloxy, aryl(C1-C4 alkyl)oxy,
C2-C10 alkylcarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyl(C1-C2 alkyl)oxy-,
C3-C10 cycloalkylcarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10 cycloalkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10 cycloalkoxycarbonyl(C1-C2 alkyl)oxy-,
aryloxycarbonyl(C1-C2 alkyl)oxy-,
aryloxycarbonyloxy(C1-C2 alkyl)oxy-,
arylcarbonyloxy(C1-C2 alkyl)oxy-,
C1-C5 alkoxy(C1-C5 alkyl)carbonyloxy(C1-C2 alkyl)oxy-,
(5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and
(R10)(R11)Nxe2x80x94(C1-C10 alkoxy)xe2x80x94;
R21 is selected from:
C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, (C3-C11 cycloalkyl)methyl, aryl, aryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 0-2 R7;
R22 is selected from:
xe2x80x94C(xe2x95x90O)xe2x80x94R18b, xe2x80x94C(xe2x95x90O)N(R18b)2, xe2x80x94C(xe2x95x90O)NHSO2R18a,
xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)R18b, xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)OR18a, and
xe2x80x94C(xe2x95x90O)NHSO2NHR18b;
Y is selected from:
xe2x80x94COR20, xe2x80x94SO3H, xe2x80x94PO3H, xe2x80x94CONHNHSO2CF3, xe2x80x94CONHSO2R18a,
xe2x80x94CONHSO2NHR18b, xe2x80x94NHCOCF3, xe2x80x94NHCONHSO2R18a, xe2x80x94NHS2R18a,
xe2x80x94OPO3H2, xe2x80x94OSO3H, xe2x80x94PO3H2, xe2x80x94SO2NHCOR18a, xe2x80x94SO2NHCO2R18a, 
m is 0-2;
n is 0-4;
p is 0-2;
r is 0-2;
with the following provisos:
(1) n and m are chosen such that the number of atoms connecting R1 and Y is in the range of 8-14,
(2) when R10 is hydrogen, C1-C4 alkyl, or phenyl(C1-C4 alkyl) and all R19 groups are H, G is N,
(3) when G is CR19, at least one R19 group cannot be H.
[2b] Preferred compounds in the second embodiment are compounds of Formula IV: 
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
R1 is selected from: 
R2 and R3 are independently selected from:
H, C1-C4 alkoxy, NR11R12, halogen, NO2, CN, CF3, C1-C6 alkyl, C3-C6 alkenyl, C3-C7 cycloalkyl,
C3-C7 cycloalkyl(C1-C4 alkyl), aryl(C1-C6 alkyl)-,
(C1-C6 alkyl)carbonyl, (C1-C6 alkoxy)carbonyl,
arylcarbonyl, and aryl substituted with 0-4 R7,
alternatively, when R2 and R3 are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3 and NO2;
R2a is selected from:
H, C1-C10 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl,
C3-C7 cycloalkyl(C1-C4 alkyl), aryl, aryl(C1-C4 alkyl)-, (C2-C7 alkyl)carbonyl, arylcarbonyl,
(C2-C10 alkoxy)carbonyl, C3-C7 cycloalkoxycarbonyl,
C7-C11 bicycloalkoxycarbonyl, aryloxycarbonyl, aryl(C1-C10 alkoxy)carbonyl,
C1-C6 alkylcarbonyloxy(C1-C4 alkoxy)carbonyl,
arylcarbonyloxy(C1-C4 alkoxy)carbonyl, and
C3-C7 cycloalkylcarbonyloxy(C1-C4 alkoxy)carbonyl;
R4 is selected from:
H, C1-C6 alkyl, C3-C7 cycloalkyl, C314 C7 cycloalkyl(C1-C4 alkyl)-, aryl, heteroaryl, aryl(C1-C6 alkyl)-, and
heteroaryl(C1-C6 alkyl)-, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2,
R6 is selected from:
H, C1-C10 alkyl, hydroxy, C1-C10 alkoxy, nitro, C1-C10 alkylcarbonyl, xe2x80x94N(R11)R12, cyano, halo, CF3, CHO, CO2R18b, C(xe2x95x90O)R18b, CONR17R18b, OC(xe2x95x90O)R10, OR10, OC(xe2x95x90O)NR10R11, NR10C(xe2x95x90O)R10, NR10C(xe2x95x90O)OR21, NR10C(xe2x95x90O)NR10R11, NR10SO2NR10R11, NR10SO2R21, S(O)pR11, SO2NR10R11,
aryl substituted with 0-3 groups selected from halogen, Cl-C6 alkoxy, C1-C6 alkyl, CF3, S(O)mMe, and xe2x80x94NMe2,
aryl(C1-C4 alkyl)-, said aryl being substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(O)pMe, and xe2x80x94NMe2, and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7;
R7 is selected from:
H, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl(C1-C4 alkyl)-, (C1-C4 alkyl)carbonyl, CO2R18a, SO2R11,
SO2NR10R11, OR10, and N(R11)R12;
U is selected from:
xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nO(CH2)mxe2x80x94, xe2x80x94NH(CH2)nxe2x80x94, xe2x80x94N(R10)C(xe2x95x90O)xe2x80x94,
xe2x80x94NHC(xe2x95x90O)(CH2)nxe2x80x94 and xe2x80x94C(xe2x95x90O)N(R10)xe2x80x94;
G is N or CR19;
R8 is selected from:
H, CO2R18b, C(xe2x95x90O)R18b, CONR17R18b,
C1-C10 alkyl substituted with 0-1 R6,
C2-C10 alkenyl substituted with 0-1 R6,
C2-C10 alkynyl substituted with 0-1 R6,
C3-C8 cycloalkyl substituted with 0-1 R6,
C5-C6 cycloalkenyl substituted with 0-1 R6,
(C1-C10 alkyl)carbonyl,
C3-C10 cycloalkyl(C1-C4 alkyl)-,
phenyl substituted with 0-3 R6,
naphthyl substituted with 0-3 R6,
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7;
R9 is selected from:
C1-C10 alkyl substituted with 0-1 R6,
C1-C10 alkoxy substituted with 0-2 R7,
H, nitro, N(R11)R12, OC(xe2x95x90O)R10, OR10, OC(xe2x95x90O)NR10OR11, NR10C(xe2x95x90O)R10), NR10C(xe2x95x90O)OR21, NR10C(xe2x95x90O)NR10R11, NR10SO2NR10R11, NR10SO2R21, hydroxy, OR22, xe2x80x94N(R10)R11, xe2x80x94N(R16)R17, aryl(C0-C6 alkyl)carbonyl, aryl(C1-C6 alkyl), heteroaryl(C1-C6 alkyl), CONR18aR20, SO2R18a, and SO2NR18aR20,
providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R7;
R10 is selected from:
H, CF3, C3-C6 alkenyl, C3-C11 cycloalkyl, aryl,
(C3-C11 cycloalkyl)methyl, aryl(C1-C4 alkyl), and C1-C10 alkyl substituted with 0-2 R6;
R11 is selected from:
H, hydroxy, C1-C8 alkyl, C3-C6 alkenyl, C3-C11 cycloalkyl, (C3-C11 cycloalkyl)methyl, C1-C6 alkoxy,
benzyloxy, aryl, heteroaryl, heteroaryl(C1-C4 alkyl)-,
aryl(C1-C4 alkyl), adamantylmethyl, and
C1-C10 alkyl substituted with 0-2 R4;
R12 is selected from:
H, C1-C6 alkyl, triphenylmethyl, methoxymethyl,
methoxyphenyldiphenylmethyl,
trimethylsilylethoxymethyl, (C1-C6 alkyl)carbonyl,
(C1-C6 alkoxy)carbonyl, (C1-C6 alkyl)aminocarbonyl,
C3-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, heteroaryl(C1-C6 alkyl)carbonyl,
heteroarylcarbonyl, aryl(C1-C6 alkyl)-,
(C1-C6 alkyl)carbonyl, arylcarbonyl, C1-C6 alkylsulfonyl, arylsulfonyl, aryl(C1-C6 alkyl)sulfonyl,
heteroarylsulfonyl, heteroaryl(C1-C6 alkyl)sulfonyl,
aryloxycarbonyl, and aryl(C1-C6 alkoxy)carbonyl,
wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and nitro;
R16 is selected from:
xe2x80x94C(xe2x95x90O)OR18a, xe2x80x94C(xe2x95x90O)R18b, xe2x80x94C(xe2x95x90O)N(R18b)2, xe2x80x94SO2R18a, and
xe2x80x94SO2N(R18b)2;
R17 is selected from:
H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, aryl(C1-C6 alkyl)-, and heteroaryl(C1-C6 alkyl);
R18a is selected from:
C1-C8 alkyl, C3-C11 cycloalkyl,
aryl(C1-C6 alkyl)-, said aryl substituted with 0-4 R19,
heteroaryl(C1-C6 alkyl)-, said heteroaryl substituted with 0-4 R19,
(C1-C6 alkyl)heteroaryl, said heteroaryl substituted with 0-4 R19,
heteroaryl substituted with 0-4 R19,
phenyl substituted with 0-4 R19, and
naphthyl substituted with 0-4 R19;
R18b is H or R18a;
R19 is selected from:
H, halogen, CF3, CO2H, CN, NO2, xe2x80x94NR11R12, OCF3,
C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
C3-C11 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-,
aryl(C1-C6 alkyl)-, C1-C6 alkoxy, C1-C4 alkoxycarbonyl,
aryl, aryl-Oxe2x80x94, aryl-SO2xe2x80x94, heteroaryl, and
heteroaryl-SO2xe2x80x94, wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF3, C1-C3 alkyl, and C1-C3 alkoxy;
R20 is selected from:
hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy,
aryloxy, aryl(C1-C4 alkyl)oxy,
C2-C10 alkylcarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyl(C1-C2 alkyl)oxy-,
C3-C10 cycloalkylcarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10 cycloalkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10 cycloalkoxycarbonyl(C1-C2 alkyl)oxy-,
aryloxycarbonyl(C1-C2 alkyl)oxy-,
aryloxycarbonyloxy(C1-C2 alkyl)oxy-,
arylcarbonyloxy(C1-C2 alkyl)oxy-,
C1-C5 alkoxy(C1-C5 alkyl)carbonyloxy(C1-C2 alkyl)oxy-,
(5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and
(R10)(R11)Nxe2x80x94(C1-C10 alkoxy)-;
R21 is selected from:
C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, (C3-C11 cycloalkyl)methyl, aryl, aryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 0-2 R7;
R22 is selected from:
xe2x80x94C(xe2x95x90O)xe2x80x94R18b, xe2x80x94C(xe2x95x90O)N(R18b)2, xe2x80x94C(xe2x95x90O)NHSO2R18a,
xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)R18b, xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)OR18a, and
xe2x80x94C (xe2x95x90O)NHSO2NHR18b;
m is 0-2;
n is 0-4; and
p is 0-2;
with the following provisos:
(1) n and m are chosen such that the number of atoms connecting R1 and xe2x80x94COR20 in Formula (IV) is in the range of 8-14,
(2) when R10 is hydrogen, C1-C4 alkyl, or phenyl(C1-C4 alkyl) and all R19 groups are H, G is N,
(3) when G is CR19, at least one R19 group cannot be H.
[2c] More preferred compounds in the second embodiment are compounds of Formula IV: 
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
R1 is selected from: 
R2 and R3 are independently selected from:
H, C1-C4 alkoxy, NR11R12, halogen, NO2, CN, CF3, C1-C6 alkyl, C3-C6 alkenyl, C3-C7 cycloalkyl,
C3-C7 cycloalkyl(C1-C4 alkyl), aryl(C1-C6 alkyl)-,
(C1-C6 alkyl)carbonyl, (C1-C6 alkoxy)carbonyl,
arylcarbonyl, and aryl substituted with 0-4 R7,
alternatively, when R2 and R3 are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3 and NO2;
R2a is selected from:
H, C1-C10 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl,
C3-C7 cycloalkyl(C1-C4 alkyl), aryl, aryl(C1-C4 alkyl)-, (C2-C7 alkyl)carbonyl, arylcarbonyl,
(C2-C10 alkoxy)carbonyl, C3-C7 cycloalkoxycarbonyl,
C7-C11 bicycloalkoxycarbonyl, aryloxycarbonyl,
aryl(C1-C10 alkoxy)carbonyl,
C1-C6 alkylcarbonyloxy(C1-C4 alkoxy)carbonyl,
arylcarbonyloxy(C1-C4 alkoxy)carbonyl, and
C3-C7 cycloalkylcarbonyloxy(C1-C4 alkoxy)carbonyl;
R4 is selected from:
H, C1-C4 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, heteroaryl, aryl(C1-C4 alkyl)-, and
heteroaryl(C1-C4 alkyl)-, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2,
R6 is selected from:
H, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, nitro, C1-C4 alkylcarbonyl, xe2x80x94N(R11)R12, cyano, halo, CF3, CHO, CO2R18b, C(xe2x95x90O)R18b, CONR17R18b, OC(xe2x95x90O)R10, OR10, OC(xe2x95x90O)NR10R11, NR10C(xe2x95x90O)R10, NR10C(xe2x95x90O)OR21, NR10C(xe2x95x90O) NR10R11, NR10SO2NR1oR11, NR10SO2R21, S(O)pR11, SO2NR10R11,
aryl substituted with 0-3 groups selected from halogen, C1-C4 alkoxy, C1-C4 alkyl, CF3, S(O)mMe, and xe2x80x94NMe2,
aryl(C1-C4 alkyl)-, said aryl being substituted with 0-3 groups selected from halogen, C1-C4 alkoxy, C1-C4 alkyl, CF3, S(O)pMe, and xe2x80x94NMe2, and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7;
R7 is selected from:
H, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl(C1-C4 alkyl)-, (C1-C4 alkyl)carbonyl, CO2R18a, SO2R11,
SO2NR10R11, OR10, and N(R11)R12;
U is selected from:
xe2x80x94(CH2)nxe2x80x94, xe2x80x94NH(CH2)nxe2x80x94, xe2x80x94N(R10)C(xe2x95x90O)xe2x80x94, and xe2x80x94NHC(xe2x95x90O)(CH2)n;
G is N or CR19;
R8 is H;
R9 is selected from:
H, nitro, N(R11)R12, OC(xe2x95x90O)R10, OR10, OC(xe2x95x90O)NR10R11, NR10C(xe2x95x90O)R10, NR10C(xe2x95x90O)OR21, NR10C(xe2x95x90O)NR10R11, NR10SO2NR10R11, NR10SO2R21, hydroxy, OR22, xe2x80x94N(R10)R11, xe2x80x94N(R16)R17, aryl(C0-C4 alkyl)carbonyl, aryl(C1-C4 alkyl), heteroaryl(C1-C4 alkyl), CONR18aR20, SO2R18a, and SO2NR18aR20,
providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R7;
R10 is selected from:
H, CF3, C3-C6 alkenyl, C3-C6 cycloalkyl, aryl,
(C3-C6 cycloalkyl)methyl, aryl(C1-C4 alkyl), and C1-C4 alkyl substituted with 0-2 R6;
R11 is selected from:
H, hydroxy, C1-C4 alkyl, C3-C6 alkenyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)methyl, C1-C4 alkoxy,
benzyloxy, aryl, heteroaryl, heteroaryl(C1-C4 alkyl)-,
aryl(C1-C4 alkyl), adamantylmethyl, and
C1-C4 alkyl substituted with 0-2 R4;
R12 is selected from:
H, C1-C4 alkyl, (C1-C4 alkyl)carbonyl, (C1-C4 alkoxy)carbonyl, phenyl(C1-C4 alkyl)-, phenylsulfonyl,
phenyloxycarbonyl, and phenyl(C1-C4 alkoxy)carbonyl,
wherein said phenyl groups are substituted with 0-2 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and nitro;
R16 is selected from:
xe2x80x94C(xe2x95x90O)OR18a, xe2x80x94C(xe2x95x90O)R18b, xe2x80x94C(xe2x95x90O)N(R18b)2, xe2x80x94SO2R18a, and
xe2x80x94SO2N (R18b)2;
R17 is selected from:
H, C1-C4 alkyl, C3-C6 cycloalkyl, C3-C6 cycloalkyl(C1-C4 alkyl)-, aryl, aryl(C1-C6 alkyl)-, and heteroaryl(C1-C6 alkyl);
R18a is selected from:
C1-C4 alkyl, C3-C6 cycloalkyl, aryl(C1-C4 alkyl)-, said aryl substituted with 0-4 R19,
heteroaryl(C1-C4 alkyl)-, said heteroaryl substituted with 0-4 R19,
(C1-C4 alkyl)heteroaryl, said heteroaryl substituted with 0-4 R19,
heteroaryl substituted with 0-4 R19,
phenyl substituted with 0-4 R19, and
naphthyl substituted with 0-4 R19;
R18b is H or R18a;
R19 is selected from:
H, halogen, CF3, CO2H, CN, NO2, xe2x80x94NR11R12, OCF3,
C1-C6 alkyl, C2-C4 alkenyl, C2-C6 alkynyl,
C3-C6 cycloalkyl, C3-C6 cycloalkyl(C1-C4 alkyl)-,
aryl(C1-C4 alkyl)-, C1-C6 alkoxy, C1-C4 alkoxycarbonyl,
aryl, aryl-Oxe2x80x94, aryl-SO2xe2x80x94, heteroaryl, and
heteroaryl-SO2xe2x80x94, wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF3, C1-C3 alkyl, and C1-C3 alkoxy;
R20 is selected from:
hydroxy, C1-C6 alkyloxy, C3-C6 cycloalkyloxy, aryloxy,
aryl(C1-C4 alkyl)oxy,
C2-C10 alkylcarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyl(C1-C2 alkyl)oxy-, C3-C10 cycloalkylcarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10 cycloalkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10 cycloalkoxycarbonyl(C1-C2 alkyl)oxy-,
aryloxycarbonyl(C1-C2 alkyl)oxy-,
aryloxycarbonyloxy(C1-C2 alkyl)oxy-,
arylcarbonyloxy(C1-C2 alkyl)oxy-,
C1-C5 alkoxy(C1-C5 alkyl)carbonyloxy(C1-C2 alkyl)oxy-,
(5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and
(R10)(R11)Nxe2x80x94(C1-C10 alkoxy)-;
R21 is selected from:
C1-C4 alkyl, C2-C6 alkenyl, C3-C6 cycloalkyl, (C3-C6 cycloalkyl)methyl, aryl, aryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 0-2 R7;
R22 is selected from:
xe2x80x94C(xe2x95x90O)xe2x80x94R18b, xe2x80x94C(xe2x95x90O)N(R18b)2, xe2x80x94C(xe2x95x90O)NHSO2R18a,
xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)R18b, xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)OR18a, and
xe2x80x94C(xe2x95x90O)NHSO2NHR18b;
m is 0-2;
n is 0-4; and
p is 0-2;
with the following provisos:
(1) n and m are chosen such that the number of atoms connecting R1 and xe2x80x94COR20 in Formula (IV) is in the range of 8-14,
(2) when R10 is hydrogen, C1-C4 alkyl, or phenyl(C1-C4 alkyl) and all R19 groups are H, G is N,
(3) when G is CR19, at least one R19 group cannot be H.
[2d] Specifically preferred compounds of the above invention are compounds of Formula IV including enantiomeric or diastereomeric forms thereof, or mixtures of enantiomeric or diastereomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof selected from the group consisting of:
3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(3,5-dimethylisoxazol-4-ylsulfonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonyl)aminopropionic acid,
3-[7-[(2-aminothiazol-4-yl)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(3,5-dimethylisoxazol-4-ylsulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((4-biphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(1-naphthylsulfonylamino)propionic acid,
3-[7-[(benzimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4-methylimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4,5-dimethylimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4,5,6,7-tetrahydrobenzimidazol-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(pyridin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-(2-aminopyridin-6-yl)-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(7-azabenzimidazol-2-yl)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(benzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionic acid,
3-[7-[(pyridin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonyl)aminopropionic acid,
3-[7-[(2-aminothiazol-4-yl)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(2-aminothiazol-4-yl)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,6,dichlorophenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((4-biphenyl)sulfonylamino)propionic acid,
3-[7-[(benzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4-methylimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4,5-dimethylimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4,5,6,7-tetrahydrobenzimidazol-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(pyridin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-(2-aminopyridin-6-yl)-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(7-azabenzimidazol-2-yl)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid
[3a] In a third embodiment of the present invention are compounds of Formula II: 
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
R1 is selected from: 
A is xe2x80x94CH2xe2x80x94 or xe2x80x94N(R12)xe2x80x94;
A1 and B are independently xe2x80x94CH2xe2x80x94 or xe2x80x94N(R10)xe2x80x94;
D is xe2x80x94N(R12)xe2x80x94 or xe2x80x94Sxe2x80x94;
Exe2x80x94F is xe2x80x94C(R2)2C(R3)2xe2x80x94 or xe2x80x94CH(R2)CH(R3)xe2x80x94;
R2 and R3 are independently selected from:
H, C1-C4 alkoxy, NR11R12, halogen, NO2, CN, CF3, C1-C6 alkyl, C3-C6 alkenyl, C3-C7 cycloalkyl,
C3-C7 cycloalkyl(C1-C4 alkyl), aryl(C1-C6 alkyl)-,
(C1-C6 alkyl)carbonyl, (C1-C6 alkoxy)carbonyl,
arylcarbonyl, and aryl substituted with 0-4 R7,
alternatively, when R2 and R3 are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3 and NO2;
R2a is selected from:
H, C1-C10 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl,
C3-C7 cycloalkyl(C1-C4 alkyl), aryl, aryl(C1-C4 alkyl)-, (C2-C7 alkyl)carbonyl, arylcarbonyl,
(C2-C10 alkoxy)carbonyl, C3-C7 cycloalkoxycarbonyl,
C7-C11 bicycloalkoxycarbonyl, aryloxycarbonyl,
aryl(C1-C10 alkoxy)carbonyl,
C1-C6 alkylcarbonyloxy(C1-C4 alkoxy)carbonyl,
arylcarbonyloxy(C1-C4 alkoxy)carbonyl, and
C3-C7 cycloalkylcarbonyloxy (C1-C4 alkoxy)carbonyl;
R4 is selected from:
H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, heteroaryl, aryl(C1-C6 alkyl)-, and
heteroaryl(C1-C6 alkyl)-, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2,
R6 is selected from:
H, C1-C10 alkyl, hydroxy, C1-C10 alkoxy, nitro, C1-C10 alkylcarbonyl, xe2x80x94N(R11)R12, cyano, halo, CF3, CHO, CO2R18b, C(xe2x95x90O)R18b, CONR17R18b, OC(xe2x95x90O)R10, OR10, OC(xe2x95x90O)NR10R11, NR10C(xe2x95x90O)R10, NR10C(xe2x95x90O)OR21, NR10C(xe2x95x90O)NR10R11, NR10SO2NR10R11, NR10SO2R21, S(O)pR11, SO2NR10R11,
aryl substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(O)mMe, and xe2x80x94NMe2,
aryl(C1-C4 alkyl)-, said aryl being substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(O)pMe, and xe2x80x94NMe2, and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7;
R7 is selected from:
H, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl(C1-C4 alkyl)-, (C1-C4 alkyl)carbonyl, CO2R18a, SO2R11,
SO2NR10R11, OR10, and N(R11)R12;
U is selected from:
xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nO(CH2)mxe2x80x94, xe2x80x94(CH2)nN(R12) (CH2)mxe2x80x94, xe2x80x94NH(CH2)n, xe2x80x94(CH2)nC(xe2x95x90O)(CH2)mxe2x80x94, xe2x80x94(CH2)nS(O)p(CH2)mxe2x80x94, xe2x80x94(CH2)nNHNH(CH2)mxe2x80x94, xe2x80x94N(R10)C(xe2x95x90O)xe2x80x94, xe2x80x94NHC(xe2x95x90O)(CH2)nxe2x80x94, xe2x80x94C(xe2x95x90O)N(R10)xe2x80x94, and xe2x80x94N(R10)S(O)pxe2x80x94;
G is N or CR19;
W is xe2x80x94C(xe2x95x90O)xe2x80x94N(R10)xe2x80x94(C1-C3 alkylene)-, in which the alkylene group is substituted by R8 and by R9:
R8 and R9 are independently selected from:
H, CO2R18b, C(xe2x95x90O)R18b, CONR17R18b,
C1-C10 alkyl substituted with 0-1 R6,
C2-C10 alkenyl substituted with 0-1 R6,
C2-C10 alkynyl substituted with 0-1 R6,
C3-C8 cycloalkyl substituted with 0-1 R6,
C5-C6 cycloalkenyl substituted with 0-1 R6,
(C1-C10 alkyl)carbonyl,
C3-C10 cycloalkyl(C1-C4 alkyl)-,
phenyl substituted with 0-3 R6,
naphthyl substituted with 0-3 R6,
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7,
C1-C10 alkoxy substituted with 0-2 R7,
hydroxy, nitro, xe2x80x94N(R10)R11, xe2x80x94N(R16)R17, aryl(C0-C6 alkyl)carbonyl, aryl(C3-C6 alkyl), heteroaryl(C1-C6 alkyl) , CONR18aR20, SO2R18a, and SO2NR18aR20,
providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R7;
R10 is selected from:
H, CF3, C3-C6 alkenyl, C3-C11 cycloalkyl, aryl,
(C3-C11 cycloalkyl)methyl, aryl(C1-C4 alkyl), and C1-C10 alkyl substituted with 0-2 R6;
R11 is selected from:
H, hydroxy, C1-C8 alkyl, C3-C6 alkenyl, C3-C11 cycloalkyl, (C3-C11 cycloalkyl)methyl, C1-C6 alkoxy,
benzyloxy, aryl, heteroaryl, heteroaryl(C1-C4 alkyl)-,
aryl(C1-C4 alkyl), adamantylmethyl, and
C1-C10 alkyl substituted with 0-2 R4;
alternatively, when R10 and R11 are both substituents on the same nitrogen atom (as in xe2x80x94NR10R11) they may be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from:
3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;
said heterocycle being substituted with 0-3 groups selected from: C1-C6 alkyl, aryl, heteroaryl, aryl(C1-C4 alkyl)-, (C1-C6 alkyl)carbonyl, (C3-C7 cycloalkyl)carbonyl, (C1-C6 alkoxy)carbonyl, aryl(C1-C4 alkoxy)carbonyl, C1-C6 alkylsulfonyl, and arylsulfonyl;
R12 is selected from:
H, C1-C6 alkyl, triphenylmethyl, methoxymethyl,
methoxyphenyldiphenylmethyl,
trimethylsilylethoxymethyl, (C1-C6 alkyl)carbonyl,
(C1-C6 alkoxy)carbonyl, (C1-C6 alkyl)aminocarbonyl,
C3-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, heteroaryl(C1-C6 alkyl)carbonyl,
heteroarylcarbonyl, aryl(C1-C6 alkyl)-,
(C1-C6 alkyl)carbonyl, arylcarbonyl, C1-C6 alkylsulfonyl, arylsulfonyl, aryl(C1-C6 alkyl)sulfonyl,
heteroarylsulfonyl, heteroaryl(C1-C6 alkyl)sulfonyl,
aryloxycarbonyl, and aryl(C1-C6 alkoxy)carbonyl,
wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and nitro;
R16 is selected from:
xe2x80x94C(xe2x95x90O)OR18a, xe2x80x94C(xe2x95x90O)R18b, xe2x80x94C(xe2x95x90O)N(R18b)2, xe2x80x94C(xe2x95x90O)NHSO2R18a,
xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)R18b, xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)OR18a,
xe2x80x94C(xe2x95x90O)NHSO2NHR18b, xe2x80x94SO2R18a, xe2x80x94SO2N(R18b)2, and
xe2x80x94SO2NHC(xe2x95x90O)OR18b ;
R17 is selected from:
H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, aryl(C1-C6 alkyl)-, and heteroaryl(C1-C6 alkyl);
R18a is selected from:
C1-C8 alkyl, C3-C11 cycloalkyl, aryl(C1-C6 alkyl)-, said aryl substituted with 0-4 R19,
heteroaryl(C1-C6 alkyl)-, said heteroaryl substituted with 0-4 R19,
(C1-C6 alkyl)heteroaryl, said heteroaryl substituted with 0-4 R19,
heteroaryl substituted with 0-4 R19,
phenyl substituted with 0-4 R19, and
naphthyl substituted with 0-4 R19;
R18b is H or R18a;
R19 is selected from:
H, halogen, CF3, CO2H, CN, NO2, xe2x80x94NR11R12, OCF3,
C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
C3-C11 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-,
aryl(C1-C6 alkyl)-, C1-C6 alkoxy, C1-C4 alkoxycarbonyl,
aryl, aryl-Oxe2x80x94, aryl-SO2xe2x80x94, heteroaryl, and
heteroaryl-SO2xe2x80x94, wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF3, C1-C3 alkyl, and C1-C3 alkoxy;
R20 is selected from:
hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy,
aryloxy, aryl(C1-C4 alkyl)oxy,
C2-C10 alkylcarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyl (C1-C2 alkyl)oxy-,
C3-C10 cycloalkylcarbonyloxy(C1-C2 alkyl)oxy - ,
C3-C10 cycloalkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10 cycloalkoxycarbonyl (C1-C2 alkyl)oxy-,
aryloxycarbonyl(Cl-C2 alkyl)oxy-,
aryloxycarbonyloxy(C1 -C2 alkyl)oxy-,
arylcarbonyloxy(C1-C2 alkyl)oxy-,
C1-C5 alkoxy(C1-C5 alkyl)carbonyloxy(C1-C2 alkyl)oxy-,
(5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and
(R10)(R11)Nxe2x80x94(C1-C10 alkoxy)-;
R21 is selected from:
C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, (C3-C11 cycloalkyl)methyl, aryl, aryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 0-2 R7;
R22 is selected from:
xe2x80x94C(xe2x95x90O)xe2x80x94R18b, xe2x80x94C(xe2x95x90O)N(R18b)2, xe2x80x94C(xe2x95x90O)NHSO2R18a,
xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)R18b, xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)OR18a, and
xe2x80x94C (xe2x95x90O)NHSO2NHR18b;
Y is selected from:
xe2x80x94COR20, xe2x80x94SO3H, xe2x80x94PO3H, xe2x80x94CONHNHSO2CF3, xe2x80x94CONHSO2R18a,
xe2x80x94CONHSO2NHR18b, xe2x80x94NHCOCF3, xe2x80x94NHCONHSO2R18a, xe2x80x94NHSO2R18a,
xe2x80x94OPO3H2, xe2x80x94OSO3H, xe2x80x94PO3H2, xe2x80x94SO2NHCOR18a, xe2x80x94SO2NHCO2R18a, 
m is 0-2;
n is 0-4;
p is 0-2; and
r is 0-2;
with the proviso that n, and m are chosen such that the number of atoms connecting R1 and Y is in the range of 8-14.
[3b] Preferred compounds of the third embodiment are those of Formula IV: 
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
R1 is selected from: 
A is xe2x80x94CH2xe2x80x94 or xe2x80x94N(R12)xe2x80x94;
A1 and B are independently xe2x80x94CH2xe2x80x94 or xe2x80x94N(R10)xe2x80x94;
D is xe2x80x94N (R12)xe2x80x94 or xe2x80x94Sxe2x80x94;
Exe2x80x94F is xe2x80x94C(R2)2C(R3)2xe2x80x94 or xe2x80x94CH(R2)CH(R3)xe2x80x94;
R2 and R3 are independently selected from:
H, C1-C4 alkoxy, NR11R12, halogen, NO2, CN, CF3, C1-C6 alkyl, C3-C6 alkenyl, C3-C7 cycloalkyl,
C3-C7 cycloalkyl(C1-C4 alkyl), aryl(C1-C6 alkyl)-,
(C1-C6 alkyl)carbonyl, (C1-C6 alkoxy)carbonyl,
arylcarbonyl, and aryl substituted with 0-4 R7,
alternatively, when R2 and R3 are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3 and N2;
R2a is selected from:
H, C1-C10 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl,
C3-C7 cycloalkyl(C1-C4 alkyl), aryl, aryl(C1-C4 alkyl)-, (C2-C7 alkyl)carbonyl, arylcarbonyl,
(C2-C10 alkoxy)carbonyl, C3-C7 cycloalkoxycarbonyl,
C7-C11 bicycloalkoxycarbonyl, aryloxycarbonyl,
aryl(C1-C10 alkoxy)carbonyl,
C1-C6 alkylcarbonyloxy(C1-C4 alkoxy)carbonyl,
arylcarbonyloxy(C1-C4 alkoxy)carbonyl, and C3-C7 cycloalkylcarbonyloxy(C1-C4 alkoxy)carbonyl;
R4 is selected from:
H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, heteroaryl, aryl(C1-C6 alkyl)-, and
heteroaryl(C1-C6 alkyl)-, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2,
R6 is selected from:
H, C1-C10 alkyl, hydroxy, C1-C10 alkoxy, nitro, C1-C10 alkylcarbonyl, xe2x80x94N(R11)R12, cyano, halo, CF3, CHO, CO2R18b, C(xe2x95x90O)R18b, CONR17R18b, OC(xe2x95x90O)R10, OR10, OC(xe2x95x90O)NR10R11, NR10C(xe2x95x90O)R10, NR10C(xe2x95x90O)OR21, NR10C(xe2x95x90O)NR10R11, NR10SO2NR10R11, NR10SO2R21, S(O)pR11, SO2NR10R11,
aryl substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(O)mMe, and xe2x80x94NMe2,
aryl(C1-C4 alkyl)-, said aryl being substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(O)pMe, and xe2x80x94NMe2, and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7;
R7 is selected from:
H, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl(C1-C4 alkyl)-, (C1-C4 alkyl)carbonyl, CO2R18a, SO2R11,
SO2NR10R11, OR10, and N(R11)R12;
U is selected from:
xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nO(CH2)mxe2x80x94, xe2x80x94NH(CH2)nxe2x80x94, xe2x80x94N(R10)C(xe2x95x90O)xe2x80x94,
xe2x80x94NHC(xe2x95x90O)(CH2)nxe2x80x94, and xe2x80x94C(xe2x95x90O)N(R10)xe2x80x94;
G is N or CR19;
R8 is selected from:
H, CO2R18b, C(xe2x95x90O)R18b, CONR17R18b,
C1-C10 alkyl substituted with 0-1 R6,
C2-C10 alkenyl substituted with 0-1 R6,
C2-C10 alkynyl substituted with 0-1 R6,
C3-C8 cycloalkyl substituted with 0-1 R6,
C5-C6 cycloalkenyl substituted with 0-1 R6,
(C1-C10 alkyl)carbonyl,
C3-C10 cycloalkyl(C1-C4 alkyl)-,
phenyl substituted with 0-3 R6,
naphthyl substituted with 0-3 R6,
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7;
R9 is selected from:
C1-C10 alkyl substituted with 0-1 R6,
C1-C10 alkoxy substituted with 0-2 R7,
H, nitro, N(R11)R12, OC(xe2x95x90O)R10, OR10, OC(xe2x95x90O)NR10R11, NR10C(xe2x95x90O)R10, NR10C(xe2x95x90O)OR21, NR2C(xe2x95x90O)NR10R11, NR10SO2NR10R11, NR10SO2R21, hydroxy, OR22, xe2x80x94N(R10)R11, xe2x80x94N(R16)R17, aryl(C0-C6 alkyl)carbonyl, aryl(C1-C6 alkyl), heteroaryl(C1-C6 alkyl), CONR18aR20, SO2R18a, and SO2NR18aR20,
providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R7;
R10 is selected from:
H, CF3, C3-C6 alkenyl, C3-C11 cycloalkyl, aryl,
(C3-C11 cycloalkyl)methyl, aryl(C1-C4 alkyl), and C1-C10 alkyl substituted with 0-2 R6;
R11 is selected from:
H, hydroxy, C1-C8 alkyl, C3-C6 alkenyl, C3-C11 cycloalkyl, (C3-C11 cycloalkyl)methyl, C1-C6 alkoxy,
benzyloxy, aryl, heteroaryl, heteroaryl(C1-C4 alkyl)-,
aryl(C1-C4 alkyl), adamantylmethyl, and
C1-C10 alkyl substituted with 0-2 R4;
R12 is selected from:
H, C1-C6 alkyl, triphenylmethyl, methoxymethyl,
methoxyphenyldiphenylmethyl,
trimethylsilylethoxymethyl, (C1-C6 alkyl)carbonyl,
(C1-C6 alkoxy)carbonyl, (C1-C6 alkyl)aminocarbonyl,
C3-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, heteroaryl(C1-C6 alkyl)carbonyl,
heteroarylcarbonyl, aryl(C1-C6 alkyl)-,
(C1-C6 alkyl)carbonyl, arylcarbonyl, C1-C6 alkylsulfonyl, arylsulfonyl, aryl(C1-C6 alkyl)sulfonyl,
heteroarylsulfonyl, heteroaryl(C1-C6 alkyl)sulfonyl,
aryloxycarbonyl, and aryl(C1-C6 alkoxy)carbonyl,
wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and nitro;
R17 is selected from:
H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, aryl(C1-C6 alkyl)-, and heteroaryl(C1-C6 alkyl);
R18a is selected from:
C1-C8 alkyl, C3-C11 cycloalkyl, aryl(C1-C6 alkyl)-, said aryl substituted with 0-4 R19,
heteroaryl(C1-C6 alkyl)-, said heteroaryl substituted with 0-4 R19,
(C1-C6 alkyl)heteroaryl, said heteroaryl substituted with 0-4 R19,
heteroaryl substituted with 0-4 R19,
phenyl substituted with 0-4 R19, and
naphthyl substituted with 0-4 R19;
R18b is H or R18a;
R19 is selected from:
H, halogen, CF3, CO2H, CN, NO2, xe2x80x94NR11R12, OCF3,
C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
C3-C11 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-,
aryl(C1-C6 alkyl)-, C1-C6 alkoxy, C1-C4 alkoxycarbonyl,
aryl, aryl-Oxe2x80x94, aryl-SO2xe2x80x94, heteroaryl, and
heteroaryl-SO2xe2x80x94, wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF3, C1-C3 alkyl, and C1-C3 alkoxy;
R20 is selected from:
hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy,
aryloxy, aryl(C1-C4 alkyl)oxy,
C2-C10 alkylcarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyl(C1-C2 alkyl)oxy-,
C3-C10 cycloalkylcarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10 cycloalkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10 cycloalkoxycarbonyl(C1-C2 alkyl)oxy-,
aryloxycarbonyl(C1-C2 alkyl)oxy-,
aryloxycarbonyloxy(C1-C2 alkyl)oxy-,
arylcarbonyloxy(C1-C2 alkyl)oxy-,
C1-C5 alkoxy(C1-C5 alkyl)carbonyloxy(C1-C2 alkyl)oxy-,
(5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and (R10)(R11)Nxe2x80x94(C1-C10 alkoxy)-;
R21 is selected from:
C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, (C3-C11 cycloalkyl)methyl, aryl, aryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 0-2 R7;
R22 is selected from:
xe2x80x94C(xe2x95x90O)R18b, xe2x80x94C(xe2x95x90O)N(R18b)2, xe2x80x94C(xe2x95x90O)NHSO2R18a,
xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)R18b, and xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)OR18a;
m is 0-2;
n is 0-4;
p is 0-2; and
r is 0-2;
with the proviso that n and m are chosen such that the number of atoms connecting R1 and COR20 of Formula (IV) is in the range of 8-14.
[3c] Preferred compounds of the third embodiment are those of Formula IV: 
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
R1 is selected from: 
A is xe2x80x94CH2xe2x80x94 or xe2x80x94N(R12)xe2x80x94;
A1 and B are independently xe2x80x94CH2xe2x80x94 or xe2x80x94N(R10)xe2x80x94;
D is xe2x80x94N(R12)xe2x80x94 or xe2x80x94Sxe2x80x94;
Exe2x80x94F is xe2x80x94C(R2)2C(R3)2xe2x80x94 or xe2x80x94CH(R2)CH(R3)2xe2x80x94;
R2 and R3 are independently selected from:
H, C1-C4 alkoxy, NR11R12 halogen, NO2, CN, CF3, C1-C6 alkyl, C3-C6 alkenyl, C3-C7 cycloalkyl,
C3-C7 cycloalkyl (C1-C4 alkyl), aryl(C1-C6 alkyl)-,
(C1-C6 alkyl)carbonyl, (C1-C6 alkoxy)carbonyl,
arylcarbonyl, and aryl substituted with 0-4 R7,
alternatively, when R2 and R3 are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3 and NO2;
R2a is selected from:
H, C1-C10 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl,
C3-C7 cycloalkyl(C1-C4 alkyl), aryl, aryl(C1-C4 alkyl)-, (C2-C7 alkyl)carbonyl, arylcarbonyl,
(C2-C10 alkoxy)carbonyl, C3-C7 cycloalkoxycarbonyl,
C7-C11 bicycloalkoxycarbonyl, aryloxycarbonyl,
aryl(C1-C10 alkoxy)carbonyl,
C1-C6 alkylcarbonyloxy(C1-C4 alkoxy)carbonyl,
arylcarbonyloxy(C1-C4 alkoxy)carbonyl, and
C3-C7 cycloalkylcarbonyloxy(C1-C4 alkoxy)carbonyl;
R4 is selected from:
H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, heteroaryl, aryl(C1-C6 alkyl)-, and
heteroaryl(C1-C6 alkyl)-, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2,
R6 is selected from:
H, C1-C10 alkyl, hydroxy, C1-C10 alkoxy, nitro, C1-C10 alkylcarbonyl, xe2x80x94N(R11)R12, cyano, halo, CF3, CHO, CO2R18b, C(xe2x95x90O)R18b, CONR17R18b, OC(xe2x95x90O)R10, OR10, OC(xe2x95x90O)NR10OR11, NR10C(xe2x95x90O)R10, NR10C(xe2x95x90O)OR21, NR10C(xe2x95x90O)NR10R11, NR10SO2NR10OR11, NR10SO2R21, S(O)pR11, SO2NR10R11,
aryl substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(O)mMe, and xe2x80x94NMe2,
aryl(C1-C4 alkyl)-, said aryl being substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(O)pMe, and xe2x80x94NMe2, and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7;
R7 is selected from:
H, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl(C1-C4 alkyl)-, (C1-C4 alkyl)carbonyl, CO2R18a, SO2R11,
SO2NR10R11, OR10, and N(R11)R12;
U is selected from:
xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nO(CH2)mxe2x80x94, xe2x80x94NH(CH2)nxe2x80x94, xe2x80x94N(R10)C(xe2x95x90O)xe2x80x94,
xe2x80x94NHC(xe2x95x90O)(CH2)nxe2x80x94, and xe2x80x94C(xe2x95x90O)N(R10)xe2x80x94;
G is N or CR19;
R8 is H;
R9 is selected from:
H, nitro, N(R11)R12, OC(xe2x95x90O)R10, OR10, OC(xe2x95x90O)NR10OR11, NR10C(xe2x95x90O)R10, NR10C(xe2x95x90O)OR21, NR10C(xe2x95x90O)NR10R11, NR10SO2NR10R11, NR10SO2R21, hydroxy, OR22, xe2x80x94N(R10)R11, xe2x80x94N(R16)R17, aryl(C1-C6 alkyl)carbonyl, aryl(C1-C6 alkyl), heteroaryl(C1-C6 alkyl), CONR18aR20, SO2R18a, and SO2NR18aR20,
providing that any of the above alkyl, cycloalkyl, aryl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R7;
R10 is selected from:
H, CF3, C3-C6 alkenyl, C3-C11 cycloalkyl, aryl,
(C3-C11 cycloalkyl)methyl, aryl(C1-C4 alkyl), and C1-C10 alkyl substituted with 0-2 R6;
R11 is selected from:
H, hydroxy, C1-C8 alkyl, C3-C6 alkenyl, C3-C11 cycloalkyl, (C3-C11 cycloalkyl)methyl, C1-C6 alkoxy,
benzyloxy, aryl, heteroaryl, heteroaryl(C1-C4 alkyl)-,
aryl(C1-C4 alkyl), adamantylmethyl, and
C1-C10 alkyl substituted with 0-2 R4;
R12 is selected from:
H, C1-C4 alkyl, (C1-C4 alkyl)carbonyl, (C1-C4 alkoxy)carbonyl, phenyl(C1-C4 alkyl)-, phenylsulfonyl,
phenyloxycarbonyl, and phenyl(C1-C4 alkoxy)carbonyl,
wherein said phenyl groups are substituted with 0-2 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and nitro;
R17 is selected from:
H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, aryl(C1-C6 alkyl)-, and heteroaryl(C1-C6 alkyl);
R18a is selected from:
C1-C8 alkyl, C3-C11 cycloalkyl,
aryl(C1-C6 alkyl)-, said aryl substituted with 0-4 R19,
heteroaryl(C1-C6 alkyl)-, said heteroaryl substituted with 0-4 R19,
(C1-C6 alkyl)heteroaryl, said heteroaryl substituted with 0-4 R19,
heteroaryl substituted with 0-4 R19,
phenyl substituted with 0-4 R19, and
naphthyl substituted with 0-4 R19;
R18b is H or R18a;
R19 is selected from:
H, halogen, CF3, CO2H, CN, NO2, xe2x80x94NR11R12, OCF3,
C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
C3-C11 cycloalkyl, C3-C7 cycloalkyl(C1-C4 
alkyl)-,
aryl(C1-C6 alkyl)-, C1-C6 alkoxy, C1-C4 alkoxycarbonyl,
aryl, aryl-Oxe2x80x94, aryl-SO2xe2x80x94, heteroaryl, and
heteroaryl-SO2xe2x80x94, wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF3, C1-C3 alkyl, and C1-C3 alkoxy;
R20 is selected from:
hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy,
aryloxy, aryl(C1-C4 alkyl)oxy,
C2-C10 alkylcarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyl(C1-C2 alkyl)oxy-,
C3-C10 cycloalkylcarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10 cycloalkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10 cycloalkoxycarbonyl(C1-C2 alkyl)oxy-,
aryloxycarbonyl(C1-C2 alkyl)oxy-,
aryloxycarbonyloxy(C1-C2 alkyl)oxy-,
arylcarbonyloxy(C1-C2 alkyl)oxy-,
C1-C5 alkoxy(C1-C5 alkyl)carbonyloxy(C1-C2 alkyl)oxy-,
(5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and (R10)(R11)Nxe2x80x94(C1-C10 alkoxy)-;
R21 is selected from:
C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, (C3-C11 cycloalkyl)methyl, aryl, aryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 0-2 R7;
R22 is selected from:
xe2x80x94C(xe2x95x90O)R18b, xe2x80x94C(xe2x95x90O)N(R18b)2, xe2x80x94C(xe2x95x90O)NHSO2R18a,
xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)R18b, and xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)OR18a;
m is 0-2;
n is 0-4;
p is 0-2; and
r is 0-2;
with the proviso that n and m are chosen such that the number of atoms connecting R1 and COR20 of Formula (IV) is in the range of 8-14.
[3d] Specifically preferred compounds of the above invention are compounds of Formula IV including enantiomeric or diastereomeric forms thereof, or mixtures of enantiomeric or diastereomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof selected from the group consisting of:
3-[7-[(imidazolin-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-(3,5-dimethylisoxazol-4-ylsulfonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonyl-amino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonyl)aminopropionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)quinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid
3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionic acid,
3-[7-[(imidazolin-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonyl)aminopropionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-methyl-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(benzyloxycarbonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butyloxycarbonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(phenylsulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-(n-butylsulfonylamino)propionic acid,
3-[7-[(tetrahydropyrimid-2-ylamino)methyl]-1-(2-phenylethyl)-6,8-difluoroquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid
[4a] In a fourth embodiment of the present invention are preferred compounds of Formula II: 
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
R1 is selected from: 
A is xe2x80x94CH2xe2x80x94 or xe2x80x94N(R12)xe2x80x94;
A1 and B are independently xe2x80x94CH2xe2x80x94 or xe2x80x94N(R10)xe2x80x94;
D is xe2x80x94N(R12)xe2x80x94 or xe2x80x94Sxe2x80x94;
Exe2x80x94F is xe2x80x94C(R2)xe2x95x90C(R3)xe2x80x94 or xe2x80x94C(R2)2C(R3)2xe2x80x94;
J is xe2x80x94C(R2)xe2x80x94 or xe2x80x94Nxe2x80x94;
K, L and M are independently xe2x80x94C(R2)xe2x80x94 or xe2x80x94C(R3)xe2x80x94;
R2 and R3 are independently selected from:
H, C1-C4 alkoxy, NR11R12, halogen, NO2, CN, CF3, C1-C6 alkyl, C3-C6 alkenyl, C3-C7 cycloalkyl,
C3-C7 cycloalkyl(C1-C4 alkyl), aryl(C1-C6 alkyl)-,
(C1-C6 alkyl)carbonyl, (C1-C6 alkoxy)carbonyl,
arylcarbonyl, and aryl substituted with 0-4 R7,
alternatively, when R2 and R3 are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3 and NO2;
R2a is selected from:
H, C1-C10 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl,
C3-C7 cycloalkyl(C1-C4 alkyl), aryl, aryl(C1-C4 alkyl)-, (C2-C7 alkyl)carbonyl, arylcarbonyl,
(C2-C10 alkoxy)carbonyl, C3-C7 cycloalkoxycarbonyl,
C7-C11 bicycloalkoxycarbonyl, aryloxycarbonyl,
aryl(C1-C10 alkoxy)carbonyl,
C1-C6 alkylcarbonyloxy(C1-C4 alkoxy)carbonyl,
arylcarbonyloxy(C1-C4 alkoxy)carbonyl, and
C3-C7 cycloalkylcarbonyloxy(C1-C4 alkoxy)carbonyl;
R4 is selected from:
H, C1-C6 alkyl, C-cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, heteroaryl, aryl(C1-C6 alkyl)-, and
heteroaryl(C1-C6 alkyl)-, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2,
R6 is selected from:
H, C1-C10 alkyl, hydroxy, C1-C10 alkoxy, nitro, C1-C10 alkylcarbonyl, xe2x80x94N(R11)R12, cyano, halo, CF3, CHO, CO2R18b, C(xe2x95x90O)R18b, CONR17R18b, OC(xe2x95x90O)R10, OR10, OC(xe2x95x90O)NR10OR11, NR10C(xe2x95x90O)R10, NR10C(xe2x95x90O)OR21, NR10C(xe2x95x90O)NR10R11, NR10SO2NR10R11, NR10SO2R21, S(O)pR11, SO2NR10R11,
aryl substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(O)mMe, and xe2x80x94NMe2,
aryl(C1-C4 alkyl)-, said aryl being substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(O)pMe, and xe2x80x94NMe2, and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7;
R7 is selected from:
H, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl(C1-C4 alkyl)-, (C1-C4 alkyl)carbonyl, CO2R18a, SO2R11,
SO2NR10R11, OR10, and N(R11)R12;
U is selected from:
xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nO(CH2)mxe2x80x94, xe2x80x94(CH2)nN(R12)(CH2)mxe2x80x94,
xe2x80x94NH(CH2)nxe2x80x94, xe2x80x94N(R10)C(xe2x95x90O)xe2x80x94, xe2x80x94NHC(xe2x95x90O)(CH2)nxe2x80x94,
xe2x80x94C(xe2x95x90O)N(R10)xe2x80x94, and xe2x80x94N(R10)S(O)pxe2x80x94;
G is N or CR19;
W is xe2x80x94C(xe2x95x90O)xe2x80x94N(R10)xe2x80x94(C1-C3 alkylene)-, in which the alkylene group is substituted by R8 and by R9:
R8 is selected from:
H, C1-C4 alkyl, hydroxy, C1-C4 alkoxy, halo, CF3, CO2H, NR10SO2R21, pyridyl, xe2x80x94N(R16)R17,
phenyl substituted with 0-3 groups selected from halogen, C1-C4 alkoxy, C1-C4 alkyl, CF3, S(O)mMe, and xe2x80x94NMe2;
phenyl(C1-C4 alkyl), said phenyl being substituted with 0-3 groups selected from halogen, C1-C4 alkoxy, C1-C4 alkyl, CF3, S(O)pMe, and xe2x80x94NMe2, and
carboxy(C1-C3 alkyl)-;
R9 is selected from:
H, CO2R18b, C(xe2x95x90O)R18b, CONR17R18b,
C1-C6 alkyl substituted with 0-1 R6,
C2-C4 alkenyl substituted with 0-1 R6,
C2-C4 alkynyl substituted with 0-1 R6,
C3-C8 cycloalkyl substituted with 0-1 R6,
C5-C6 cycloalkenyl substituted with 0-1 R6,
(C1-C4 alkyl)carbonyl,
C3-C10 cycloalkyl(C1-C4 alkyl)-,
phenyl substituted with 0-3 R6,
naphthyl substituted with 0-3 R6,
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7,
C1-C4 alkoxy substituted with 0-2 R7,
hydroxy, C02H, nitro, xe2x80x94N(R10)R11, xe2x80x94N(R16)R17, phenyl(C0-C4 alkyl)carbonyl, phenyl(C1-C4 alkyl)-, heteroaryl(C1-C6 alkyl)-, CONR18aR20, SO2R18a, and SO2NR18aR20,
providing that any of the above alkyl, cycloalkyl, phenyl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R7;
R10 is selected from:
H, CF3, C3-C6 alkenyl, C3-C11 cycloalkyl, phenyl,
(C3-C11 cycloalkyl)methyl, phenyl(C1-C4 alkyl), and
C1-C10 alkyl substituted with 0-2 R6;
R11 is selected from:
H, hydroxy, C1-C8 alkyl, C3-C6 alkenyl, C3xe2x80x94C11 cycloalkyl, (C3-C11 cycloalkyl)methyl, C1-C6 alkoxy,
benzyloxy, aryl, heteroaryl, heteroaryl(C1-C4 alkyl)-,
aryl(Cl-C4 alkyl), adamantylmethyl, and
C1-C10 alkyl substituted with 0-2 R4;
alternatively, when R10 and R11 are both substituents on the same nitrogen atom (as in xe2x80x94NR10R11) they may be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from:
3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;
said heterocycle being substituted with 0-3 groups selected from: C1-C6 alkyl, aryl, heteroaryl, aryl(C1-C4 alkyl)-, (C1-C6 alkyl)carbonyl, (C3-C7 cycloalkyl)carbonyl, (C1-C6 alkoxy)carbonyl, aryl(C1-C4 alkoxy)carbonyl, C1-C6 alkylsulfonyl, and arylsulfonyl;
R12 is selected from:
H, C1-C6 alkyl, triphenylmethyl, methoxymethyl,
methoxyphenyldiphenylmethyl,
trimethylsilylethoxymethyl, (C1-C6 alkyl)carbonyl,
(C1-C6 alkoxy)carbonyl, (C1-C6 alkyl)aminocarbonyl,
C3-C4 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, heteroaryl(C1-C6 alkyl)carbonyl,
heteroarylcarbonyl, aryl(C1-C6 alkyl)-,
(C1-C6 alkyl)carbonyl, arylcarbonyl, C1-C6 alkylsulfonyl, arylsulfonyl, aryl(C1-C6 alkyl)sulfonyl,
heteroarylsulfonyl, heteroaryl(C1-C6 alkyl)sulfonyl,
aryloxycarbonyl, and aryl(C1-C6 alkoxy)carbonyl,
wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and nitro;
R14 is selected from:
H, C1-C4 alkyl, and phenyl(C1-C4 alkyl);
R16 is selected from:
xe2x80x94C(xe2x95x90O)OR18a, C(xe2x95x90O)R18b, xe2x80x94C(xe2x95x90O)N(R18b)2, xe2x80x94C(xe2x95x90O)NHSO2R18a,
xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)R18b, xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)OR18a,
xe2x80x94C(xe2x95x90O)NHSO2NHR18b, xe2x80x94SO2R18a, xe2x80x94SO2N(R18b)2, and
xe2x80x94SO2NHC(xe2x95x90O)OR18b;
R17 is selected from:
H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, aryl(C1-C6 alkyl)-, and heteroaryl(C1-C6 alkyl);
R18a is selected from:
C1-C6 alkyl, aryl-, fluoro(C3-C6 alkyl), aryl(C1-C4 alkyl-, di(C1-C4 alkyl)amino(C1-C4 alkyl),
morpholino(C1-C4 alkyl), piperidino(C1-C4 alkyl), Nxe2x80x94(C1-C4 alkyl)piperidino(C1-C4 alkyl), and phenyl substituted by one or two optional groups selected from C1-C4 alkyl, C1-C4 alkoxy, and halogen;
R18b is H or R18a;
R19 is selected from:
H, halogen, CF3, CO2H, CN, NO2, xe2x80x94NR11R12, OCF3,
C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
C3-C11 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-,
aryl(C1-C6 alkyl)-, C1-C6 alkoxy, C1-C4 alkoxycarbonyl,
aryl, aryl-Oxe2x80x94, aryl-SO2xe2x80x94, heteroaryl, and
heteroaryl-SO2xe2x80x94, wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF3, C1-C3 alkyl, and C1-C3 alkoxy;
R20 is selected from:
hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy,
aryloxy, aryl(C1-C4 alkyl)oxy,
C2-C10 alkylcarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyl(C1-C2 alkyl)oxy-,
C3-C10 cycloalkylcarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10 cycloalkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10cycloalkoxycarbonyl(C1-C2 alkyl)oxy-,
aryloxycarbonyl(C1-C2 alkyl)oxy-,
aryloxycarbonyloxy(C1-C2 alkyl)oxy-,
arylcarbonyloxy(C1-C2 alkyl)oxy-,
C1-C5 alkoxy(C1-C5 alkyl)carbonyloxy(C1-C2 alkyl)oxy-,
(5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and
(R10)(R11)Nxe2x80x94(C1-C10 alkoxy)-;
R21 is selected from:
C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, (C3-C11 cycloalkyl)methyl, aryl, aryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 0-2 R7;
Y is selected from:
xe2x80x94COR20, xe2x80x94CONHNHSO2CF3, xe2x80x94CONHSO2R18a, xe2x80x94CONHSO2NHR18b ,
xe2x80x94NHCOCF3, and xe2x80x94NHSO2R18a;
m is 0-2;
n is 0-4;
p is 0-2;
r is 0-2;
with the proviso that n and m are chosen such that the number of atoms connecting R1 and Y is in the range of 8-14.
[4b] Preferred compounds of the fourth embodiment of the present invention are those of Formula III: 
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
R1 is selected from: 
A is xe2x80x94CH2xe2x80x94 or xe2x80x94N(R12)xe2x80x94;
A1 and B are independently xe2x80x94CH2xe2x80x94 or xe2x80x94N(R10)xe2x80x94;
D is xe2x80x94N(R12)xe2x80x94 or xe2x80x94Sxe2x80x94;
Exe2x80x94F is xe2x80x94C(R2)xe2x95x90C(R3)xe2x80x94 or xe2x80x94C(R2)2C(R3)2xe2x80x94;
R2 and R3 are independently selected from:
H, C1-C4 alkoxy, NR11R12, halogen, NO2, CN, CF3, C1-C6 alkyl, C3-C6 alkenyl, C3-C7 cycloalkyl,
C3-C7 cycloalkyl(C1-C4 alkyl), aryl(C1-C6 alkyl)-,
(C1-C6 alkyl)carbonyl, (C1-C6 alkoxy)carbonyl,
arylcarbonyl, and aryl substituted with 0-4 R7,
alternatively, when R2 and R3 are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3 and N2;
R2a is selected from:
H, C1-C10 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl,
C3-C7 cycloalkyl(C1-C4 alkyl), aryl, aryl(C1-C4 alkyl)-,
(C2-C7alkyl)carbonyl, arylcarbonyl,
(C2-C10 alkoxy)carbonyl, C3-C7 cycloalkoxycarbonyl,
C7-C11 bicycloalkoxycarbonyl, aryloxycarbonyl,
aryl(C1-C10 alkoxy)carbonyl,
C1-C6 alkylcarbonyloxy(C1-C4 alkoxy)carbonyl,
arylcarbonyloxy(C1-C4 alkoxy)carbonyl, and
C3-C7 cycloalkylcarbonyloxy(C1-C4 alkoxy)carbonyl;
R4 is selected from:
H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, heteroaryl, aryl(C1-C6 alkyl)-, and
heteroaryl(C1-C6 alkyl)-, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2,
R6 is selected from:
H, C1-C10 alkyl, hydroxy, C1-C10 alkoxy, nitro, C1-C10 alkylcarbonyl, xe2x80x94N(R11)R12, cyano, halo, CF3, CHO, CO2R18b, C(xe2x95x90O)R18b, CONR17R18b, OC(xe2x95x90O)R10, OR10, OC(xe2x95x90O)NR10R11, NR10C(xe2x95x90O)R10, NR10C(xe2x95x90O)OR21, NR10C(xe2x95x90O)NR10R11, NR10SO2NR10R11, NR10SO2R21, S(O)pR11, SO2NR10R11,
aryl substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(O)mMe, and xe2x80x94NMe2,
aryl(C1-C4 alkyl)-, said aryl being substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(O)pMe, and xe2x80x94NMe2, and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7;
R7 is selected from:
H, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl(C1-C4 alkyl)-, (C1-C4 alkyl)carbonyl, CO2R18a, SO2R11,
SO2NR10R11, OR10, and N(R11)R12;
U is selected from:
xe2x80x94(CH2)nxe2x80x94, xe2x80x94(CH2)nO(CH2)mxe2x80x94, xe2x80x94(CH2)nN(R12)(CH2)mxe2x80x94,
xe2x80x94NH(CH2)nxe2x80x94, xe2x80x94N(R10)C(xe2x95x90O)xe2x80x94, and xe2x80x94NHC(xe2x95x90O)(CH2)nxe2x80x94;
G is N or CR19;
R8 is H;
R9 is selected from:
H, CO2R18b, C(xe2x95x90O)R18b, CONR17R18b,
C1-C6 alkyl substituted with 0-1 R6,
C2-C4 alkenyl substituted with 0-1 R6,
C2-C4 alkynyl substituted with 0-1 R6,
C3-C8 cycloalkyl substituted with 0-1 R6,
C5-C6 cycloalkenyl substituted with 0-1 R6,
(C1-C4 alkyl)carbonyl,
C3-C10 cycloalkyl(C1-C4 alkyl)-,
phenyl substituted with 0-3 R6,
naphthyl substituted with 0-3 R6,
a 5-10 membered heterocyclic ring containing 1 -3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7,
C1-C4 alkoxy substituted with 0-2 R7,
hydroxy, CO2H, nitro, xe2x80x94N(R10)R11, xe2x80x94N(R16)R17, phenyl(C0-C4 alkyl)carbonyl, phenyl(C1-C4 alkyl)-, heteroaryl(C1-C6 alkyl)-, CONR18aR20, SO2R18a, and SO2NR18aR20,
providing that any of the above alkyl, cycloalkyl, phenyl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R7;
R10 is selected from:
H, CF3, C3-C6 alkenyl, C3-C11 cycloalkyl, phenyl,
(C3-C11 cycloalkyl)methyl, phenyl(C1-C4 alkyl), and
C1-C10 alkyl substituted with 0-2 R6;
R11 is selected from:
H, hydroxy, C1-C8 alkyl, C3-C6 alkenyl, C3-C11 cycloalkyl, (C3-C11 cycloalkyl)methyl, C1-C6 alkoxy,
benzyloxy, aryl, heteroaryl, heteroaryl(C1-C4 alkyl)-,
aryl(C1-C4 alkyl), adamantylmethyl, and
C1-C10 alkyl substituted with 0-2 R4;
alternatively, when R10 and R11 are both substituents on the same nitrogen atom (as in xe2x80x94NR10R11) they may be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from:
3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;
said heterocycle being substituted with 0-3 groups selected from: C1-C6 alkyl, aryl, heteroaryl, aryl(C1-C4 alkyl)-, (C1-C6 alkyl)carbonyl, (C3-C7 cycloalkyl)carbonyl, (C1-C6 alkoxy)carbonyl, aryl(C1-C4 alkoxy)carbonyl, C1-C6 alkylsulfonyl, and arylsulfonyl;
R12 is selected from:
H, C1-C6 alkyl, triphenylmethyl, methoxymethyl,
methoxyphenyldiphenylmethyl,
trimethylsilylethoxymethyl, (C1-C6 alkyl)carbonyl,
(C1-C6 alkoxy)carbonyl, (C1-C6 alkyl)aminocarbonyl,
C3-C6 alkenyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, heteroaryl(C1-C6 alkyl)carbonyl,
heteroarylcarbonyl, aryl(C1-C6 alkyl)-,
(C1-C6 alkyl)carbonyl, arylcarbonyl, C1-C6 
alkylsulfonyl, arylsulfonyl, aryl(C1-C6 alkyl)sulfonyl,
heteroarylsulfonyl, heteroaryl(C1-C6 alkyl)sulfonyl,
aryloxycarbonyl, and aryl(C1-C6 alkoxy)carbonyl,
wherein said aryl groups are substituted with 0-2 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and nitro;
R14 is selected from H, CH3, benzyl and phenylethyl;
R16 is selected from:
xe2x80x94C(xe2x95x90O)OR18a, xe2x80x94C(xe2x95x90O)R18b, xe2x80x94C(xe2x95x90O)N(R18b)2, xe2x80x94C(xe2x95x90O)NHSO2R18a,
xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)R18b, xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)OR18a,
xe2x80x94C(xe2x95x90O)NHSO2NHR18b, xe2x80x94SO2R18a, xe2x80x94SO2N(R18b)2, and
xe2x80x94SO2NHC(xe2x95x90O)OR18b;
R17 is selected from:
H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, aryl(Cl-C6 alkyl)-, and heteroaryl(C1-C6 alkyl);
R18a is selected from:
C1-C6 alkyl, aryl-, fluoro(C3-C6 alkyl), aryl(C1-C4 alkyl-, di(C1-C4 alkyl)amino(C1-C4 alkyl),
morpholino(C1-C4 alkyl), piperidino(C1-C4 alkyl), Nxe2x80x94(C1-C4 alkyl)piperidino(C1-C4 alkyl), and phenyl substituted by one or two optional groups selected from C1-C4 alkyl, Cl-C4 alkoxy, and halogen;
R18b is H or R18a;
R19 is selected from:
H, halogen, CF3, CO2H, CN, NO2, xe2x80x94NR11R12, OCF3,
C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
C3-C11 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-,
aryl(C1-C6 alkyl)-, C1-C6 alkoxy, C1-C4 alkoxycarbonyl,
aryl, aryl-Oxe2x80x94, aryl-SO2xe2x80x94, heteroaryl, and
heteroaryl-SO2xe2x80x94, wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF3, C1-C3 alkyl, and C1-C3 alkoxy;
R20 is selected from:
hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy,
aryloxy, aryl(C1-C4 alkyl)oxy,
C2-C10 alkylcarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyl(C1-C2 alkyl)oxy-,
C3-C10 cycloalkylcarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10 cycloalkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10 cycloalkoxycarbonyl(C1-C2 alkyl)oxy-,
aryloxycarbonyl(C1-C2 alkyl)oxy-,
aryloxycarbonyloxy(C1-C2 alkyl)oxy-,
arylcarbonyloxy(C1-C2 alkyl)oxy-,
C1-C5 alkoxy(C1-C5 alkyl)carbonyloxy(C1-C2 alkyl)oxy-,
(5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and
(R10)(R11)Nxe2x80x94(C1-C10 alkoxy)-;
R21 is selected from:
C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, (C3-C11 cycloalkyl)methyl, aryl, aryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 0-2 R7;
m is 0-2;
n is 0-4;
p is 0-2; and
r is 0-2;
with the following provisos:
(1) n and m are chosen such that the number of atoms connecting R1 and COR20 of Formula (III) is in the range of 8-14; and
(2) one of the groups R8 or R9 must be hydrogen.
[4c] More preferred compounds of the fourth embodiment of the present invention are those of Formula III: 
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
R1 is selected from: 
A is xe2x80x94CH2xe2x80x94 or xe2x80x94N(R12)xe2x80x94;
A1 and B are independently xe2x80x94CH2xe2x80x94 or xe2x80x94N(R10)xe2x80x94;
D is xe2x80x94N(R12)xe2x80x94 or xe2x80x94Sxe2x80x94;
E-F is xe2x80x94C(R2)xe2x95x90C(R3)xe2x80x94 or xe2x80x94C(R2)2C(R3)2xe2x80x94;
R2 and R3 are independently selected from:
H, C1-C4 alkoxy, NR11R12, halogen, NO2, CN, CF3, C1-C6 alkyl, C3-C6 alkenyl, C3-C7 cycloalkyl,
C3-C7 cycloalkyl(C1-C4 alkyl), aryl(C1-C6 akyl)-,
(C1-C6 alkyl)carbonyl, (C1-C6 alkoxy)carbonyl,
arylcarbonyl, and aryl substituted with 0-4 R7,
alternatively, when R2 and R3 are substituents on adjacent atoms, they can be taken together with the carbon atoms to which they are attached to form a 5-7 membered carbocyclic or 5-7 membered heterocyclic aromatic or nonaromatic ring system, said carbocyclic or heterocyclic ring being substituted with 0-2 groups selected from C1-C4 alkyl, C1-C4 alkoxy, halo, cyano, amino, CF3 and NO2;
R4 is selected from:
H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, heteroaryl, aryl(C1-C6 alkyl)-, and
heteroaryl(C1-C6 alkyl)-, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2,
R6 is selected from:
H, C1-C10 alkyl, hydroxy, C1-C10 alkoxy, nitro, C1-C10 alkylcarbonyl, xe2x80x94N(R11)R12, cyano, halo, CF3, CHO, CO2R18b, C(xe2x95x90O)R18b, CONR17R18b, OC(xe2x95x90O)R10, OR10, OC(xe2x95x90O)NR10R11, NR10C(xe2x95x90O)R10, NR10C(xe2x95x90O)OR21, NR10C(xe2x95x90O) NR10R11, NR10SO2NR10R11, NR10SO2R21, S(O)pR11, SO2NR10R11,
aryl substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(O)mMe, and xe2x80x94NMe2,
aryl(C1-C4 alkyl)-, said aryl being substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(O)pMe, and xe2x80x94NMe2, and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7;
R7 is selected from:
H, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl(C1-C4 alkyl)-, (C1-C4 alkyl)carbonyl, CO2R18a, SO2R11,
SO2NR10R11, OR10, and N(R11)R12;
U is selected from:
xe2x80x94(CH2)nxe2x80x94, xe2x80x94NH(CH2)nxe2x80x94, xe2x80x94N(R10)C(xe2x95x90O)xe2x80x94, and xe2x80x94NHC(xe2x95x90O)(CH2)nxe2x80x94;
G is N or CR19;
R8 is H;
R9 is selected from:
H, hydroxy, CO2H, nitro, xe2x80x94N(R10)R11, xe2x80x94N(R16)R17, phenyl(C0-C4 alkyl)carbonyl, phenyl(C1-C4 alkyl)-, heteroaryl(C1-C6 alkyl)-, CONR18aR20, SO2R18a, and SO2NR18aR20,
providing that any of the above phenyl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R7;
R10 is selected from:
H, CF3, C3-C6 alkenyl, C3-C11 cycloalkyl, phenyl,
(C3-C11 cycloalkyl)methyl, phenyl(C1-C4 alkyl), and
C1-C10 alkyl substituted with 0-2 R6;
R11 is selected from:
H, hydroxy, C1-C8 alkyl, C3-C6 alkenyl, C3-C11 cycloalkyl, (C3-C11 cycloalkyl)methyl, C1-C6 alkoxy,
benzyloxy, aryl, heteroaryl, heteroaryl(C1-C4 alkyl)-,
aryl(C1-C4 alkyl), adamantylmethyl, and
C1-C10 alkyl substituted with 0-2 R4;
alternatively, when R10 and R11 are both substituents on the same nitrogen atom (as in xe2x80x94NR10R11) they may be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from:
3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;
said heterocycle being substituted with 0-3 groups selected from: C1-C6 alkyl, aryl, heteroaryl, aryl(C1-C4 alkyl)-, (C1-C6 alkyl)carbonyl, (C3-C7 cycloalkyl)carbonyl, (C1-C6 alkoxy)carbonyl, aryl(C1-C4 alkoxy)carbonyl, C1-C6 alkylsulfonyl, and arylsulfonyl;
R12 is selected from:
H, C1-C4 alkyl, (C1-C4 alkyl)carbonyl, (C1-C4 alkoxy)carbonyl, phenyl(C1-C4 alkyl)-, phenylsulfonyl,
phenyloxycarbonyl, and phenyl(C1-C4 alkoxy)carbonyl,
wherein said phenyl groups are substituted with 0-2 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and nitro;
R14 is selected from H, CF3, CH3, and benzyl;
R16 is selected from:
xe2x80x94C(xe2x95x90O)OR18a, xe2x80x94C(xe2x95x90O)R18b, xe2x80x94C(xe2x95x90O)N(R18b)2, xe2x80x94C(xe2x95x90O)NHSO2R18a,
xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)R18b, xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)OR18a,
xe2x80x94C(xe2x95x90O)NHSO2NHR18b, xe2x80x94SO2R18a, xe2x80x94SO2N(R18b)2, and
xe2x80x94SO2NHC(xe2x95x90O)OR18b;
R17 is selected from:
H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, aryl(C1-C6 alkyl)-, and heteroaryl(C1-C6 alkyl);
R18a is selected from:
C1-C6 alkyl, aryl-, fluoro (C3-C6 alkyl), aryl(C1-C4 alkyl-, di(C1-C4 alkyl)amino(C1-C4 alkyl),
morpholino(C1-C4 alkyl), piperidino(C1-C4 alkyl), Nxe2x80x94(C1-C4 alkyl)piperidino(C1-C4 alkyl), and phenyl substituted by one or two optional groups selected from C1-C4 alkyl, C1-C4 alkoxy, and halogen;
R18b is H or R18a;
R19 is selected from:
H, halogen, CF3, CO2H, CN, NO2, xe2x80x94NR11R12, OCF3,
C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
C3-C11 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-,
aryl(C1-C6 alkyl)-, C1-C6 alkoxy, C1-C4 alkoxycarbonyl,
aryl, aryl-Oxe2x80x94, aryl-SO2xe2x80x94, heteroaryl, and
heteroaryl-SO2xe2x80x94, wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF3, C1-C3 alkyl, and C1-C3 alkoxy;
R20 is selected from:
hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy,
aryloxy, aryl(C1-C4 alkyl)oxy,
C2-C10 alkylcarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyl(C1-C2 alkyl)oxy-,
C3-C10 cycloalkylcarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10 cycloalkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10 cycloalkoxycarbonyl(C1-C2 alkyl)oxy-,
aryloxycarbonyl(C1-C2 alkyl)oxy-,
aryloxycarbonyloxy( C1-C2 alkyl)oxy-,
arylcarbonyloxy(C1-C2 alkyl)oxy-,
C1-C5 alkoxy(C1-C5 alkyl)carbonyloxy(C1-C2 alkyl)oxy-,
(5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and
(R10)(R11)Nxe2x80x94(C1-C10 alkoxy)-;
R21 is selected from:
C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, (C3-C11 cycloalkyl)methyl, aryl, aryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 0-2 R7;
m is 0-2;
n is 0-4;
p is 0-2; and
r is 0-2;
with the following provisos:
1) n and m are chosen such that the number of atoms connecting R1 and COR20 of Formula (III) is in the range of 8-14; and
(2) one of the groups R8 or R9 must be hydrogen.
[4d] Further preferred compounds of the fourth embodiment of the present invention are those of Formula III: 
including stereoisomeric forms thereof, or mixtures of stereoisomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof wherein:
R1 is selected from: 
R4 is selected from:
H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, heteroaryl, aryl(C1-C6 alkyl)-, and
heteroaryl(C1-C6 alkyl)-, wherein said aryl or heteroaryl groups are substituted with 0-2 substituents independently selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, F, Cl, Br, CF3, and NO2,
R6 is selected from:
H, C1-C10 alkyl, hydroxy, C1-C10 alkoxy, nitro, C1-C10 alkylcarbonyl, xe2x80x94N(R11)R12, cyano, halo, CF3, CHO, CO2R18b, C(xe2x95x90O)R18b, CONR17R18b, OC(xe2x95x90O)R10, OR10, OC(xe2x95x90O)NR10R11, NR10C(xe2x95x90O)R10, NR10C(xe2x95x90O)OR21, NR10C(xe2x95x90O)NR10R11, NR10SO2NR10R11, NR10SO2R21, S(O)pR11, SO2NR10R11,
aryl substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(O)mMe, and xe2x80x94NMe2,
aryl(C1-C4 alkyl)-, said aryl being substituted with 0-3 groups selected from halogen, C1-C6 alkoxy, C1-C6 alkyl, CF3, S(O)pMe, and xe2x80x94NMe2, and
a 5-10 membered heterocyclic ring containing 1-3 N, O, or S heteroatoms, wherein said heterocyclic ring may be saturated, partially saturated, or fully unsaturated, said heterocyclic ring being substituted with 0-2 R7;
R7 is selected from:
H, hydroxy, C1-C4 alkyl, C1-C4 alkoxy, aryl, aryl(C1-C4 alkyl)-, (C1-C4 alkyl)carbonyl, CO2R18a, SO2R11,
SO2NR10R11, OR10, and N(R11)R12;
U is selected from:
xe2x80x94(CH2)nxe2x80x94, xe2x80x94NH(CH2)nxe2x80x94, xe2x80x94N(R10)C(xe2x95x90O)xe2x80x94, and xe2x80x94NHC(xe2x95x90O)(CH2)nxe2x80x94;
G is N or CR19;
R8 is H;
R9 is selected from:
H, hydroxy, CO2H, xe2x80x94N(R10)R11, xe2x80x94N(R16)R17, phenyl(C0-C4 alkyl)carbonyl, phenyl(C1-C4 alkyl)-, heteroaryl(C1-C6 alkyl)-, CONR18aR20, SO2R18a, and SO2NR18aR20,
providing that any of the above phenyl or heteroaryl groups may be unsubstituted or substituted independently with 1-2 R7;
R10 is selected from:
H, CF3, C3-C6 alkenyl, C3-C11 cycloalkyl, phenyl, (C3-C11 cycloalkyl)methyl, phenyl(C1-C4 alkyl), and C1-C10 alkyl substituted with 0-2 R6;
R11 is selected from:
H, hydroxy, C1-C8 alkyl, C3-C6 alkenyl, C3-C11 cycloalkyl, (C3-C11 cycloalkyl)methyl, C1-C6 alkoxy, benzyloxy, aryl, heteroaryl, heteroaryl(C1-C4 alkyl)-, aryl(C1-C4 alkyl), adamantylmethyl, and C1-C10 alkyl substituted with 0-2 R4;
alternatively, when R10 and R11 are both substituents on the same nitrogen atom (as in xe2x80x94NR10R11) they may be taken together with the nitrogen atom to which they are attached to form a heterocycle selected from:
3-azabicyclononyl, 1,2,3,4-tetrahydro-1-quinolinyl, 1,2,3,4-tetrahydro-2-isoquinolinyl, 1-piperidinyl, 1-morpholinyl, 1-pyrrolidinyl, thiamorpholinyl, thiazolidinyl, and 1-piperazinyl;
said heterocycle being substituted with 0-3 groups selected from: C1-C6 alkyl, aryl, heteroaryl, aryl (C1-C4 alkyl)-, (C1-C6 alkyl)carbonyl, (C3-C7 cycloalkyl)carbonyl, (C1-C6 alkoxy)carbonyl, aryl(C1-C4 alkoxy)carbonyl, C1-C6 alkylsulfonyl, and arylsulfonyl;
R12 is selected from:
H, C1-C4 alkyl, (C1-C4 alkyl)carbonyl, (C1-C4 alkoxy)carbonyl, phenyl(C1-C4 alkyl)-, phenylsulfonyl, phenyloxycarbonyl, and phenyl(C1-C4 alkoxy)carbonyl, wherein said phenyl groups are substituted with 0-2 substituents selected from the group consisting of C1-C4 alkyl, C1-C4 alkoxy, halo, CF3, and nitro;
R14 is selected from H, CF3, CH3, and benzyl;
R16 is selected from:
xe2x80x94C(xe2x95x90O)OR18a, xe2x80x94C(xe2x95x90O)R18b, xe2x80x94C(xe2x95x90O)N(R18b)2, xe2x80x94C(xe2x95x90O)NHSO2R18a, xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)R18b, xe2x80x94C(xe2x95x90O)NHC(xe2x95x90O)OR18a, xe2x80x94C(xe2x95x90O)NHSO2NHR18b, xe2x80x94SO2R18a, xe2x80x94SO2N(R18b)2, and xe2x80x94SO2NHC(xe2x95x90O)OR18b;
R17 is selected from:
H, C1-C6 alkyl, C3-C7 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-, aryl, aryl(C1-C6 alkyl)-, and heteroaryl(C1-C6 alkyl);
R18a is selected from:
C1-C6 alkyl, aryl-, fluoro(C3-C6 alkyl), aryl(C1-C4 alkyl-, di(C1-C4 alkyl)amino(C1-C4 alkyl), morpholino(C1-C4 alkyl), piperidino(C1-C4 alkyl), Nxe2x80x94(C1-C4 alkyl)piperidino(C1-C4 alkyl), and phenyl substituted by one or two optional groups selected from C1-C4 alkyl, C1-C4 alkoxy, and halogen;
R18b is H or R18a;
R19 is selected from:
H, halogen, CF3, CO2H, CN, NO2, xe2x80x94NR11R12, OCF3,
C1-C8 alkyl, C2-C6 alkenyl, C2-C6 alkynyl,
C3-C11 cycloalkyl, C3-C7 cycloalkyl(C1-C4 alkyl)-,
aryl(C1-C6 alkyl)-, C1-C6 alkoxy, C1-C4 alkoxycarbonyl,
aryl, aryl-Oxe2x80x94, aryl-SO2xe2x80x94, heteroaryl, and
heteroaryl-SO2-, wherein said aryl and heteroaryl groups are substituted with 0-4 groups selected from hydrogen, halogen, CF3, C1-C3 alkyl, and C1-C3 alkoxy;
R20 is selected from:
hydroxy, C1-C10 alkyloxy, C3-C11 cycloalkyloxy,
aryloxy, aryl(C1-C4 alkyl)oxy,
C2-C10 alkylcarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C2-C10 alkoxycarbonyl(C1-C2 alkyl)oxy-,
C3-C10 cycloalkylcarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10 cycloalkoxycarbonyloxy(C1-C2 alkyl)oxy-,
C3-C10 cycloalkoxycarbonyl(C1-C2 alkyl)oxy-,
aryloxycarbonyl(C1-C2 alkyl)oxy-,
aryloxycarbonyloxy(C1-C2 alkyl)oxy-,
arylcarbonyloxy(C1-C2 alkyl)oxy-,
C1-C5 alkoxy(C1-C5 alkyl)carbonyloxy(C1-C2 alkyl)oxy-,
(5-(C1-C5 alkyl)-1,3-dioxa-cyclopenten-2-one-yl)methyloxy,
(5-aryl-1,3-dioxa-cyclopenten-2-one-yl)methyloxy, and
(R10)(R11)Nxe2x80x94(C1-C10 alkoxy)-;
R21 is selected from:
C1-C8 alkyl, C2-C6 alkenyl, C3-C11 cycloalkyl, (C3-C11 cycloalkyl)methyl, aryl, aryl(C1-C4 alkyl)-, and C1-C10 alkyl substituted with 0-2 R7;
m is 0-2;
n is 0-4;
p is 0-2; and
r is 0-2;
with the following provisos:
(1) n and m are chosen such that the number of atoms connecting R1 and COR20 in Formula (III) is in the range of 8-14; and
(2) one of the groups R8 or R9 must be hydrogen.
[4e] Specifically preferred compounds of the above invention are compounds of Formula III including enantiomeric or diastereomeric forms thereof, or mixtures of enantiomeric or diastereomeric forms thereof, or pharmaceutically acceptable salt or prodrug forms thereof selected from the group consisting of:
3-[7-[(imidazol-2-ylamino)methyl]-1-cyclopropylylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-cyclopentylquinoline-4-one-3-ylcarbonylamino]-2-((4-phenylbenzene)sulfonylamino)propionic acid,
3-[7-[(benzimidazol-2-ylamino)methyl]-1-methylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(4,5-dimethylimidazol-2-ylamino)methyl]-1-trifluoromethylquinoline-4-one-3-ylcarbonylamino]-2-((2,6-dichlorophenyl)sulfonylamino)propionic acid,
3-[7-(2-aminopyridin-6-yl)-1-phenylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl) sulfonylamino)propionic acid,
3-[7-[(7-azabenzimidazol-2-yl)methyl]-1-cyclohexylquinoline-4-one-3-ylcarbonylamino]-2-((2,4,6-trimethylphenyl)sulfonylamino)propionic acid,
3-[7-[(imidazol-2-ylamino)methyl]-1-cyclopropylquinoline-4-one-3-ylcarbon-ylamino]-2-((2,2-dichloro-4-phenylbenzene)sulfonylamino) propionic acid,
In a fifth embodiment the present invention provides for a method for the treatment of cancer metastasis, diabetic retinopathy, neovascular glaucoma, thrombosis, restenosis, osteoporosis, or macular degeneration which comprises administering to a host in need of such treatment a therapeutically effective amount of a compound of Formula (I) or Formula (II).
In a sixth embodiment the present invention provides for a pharmaceutical composition comprising a pharmaceutically acceptable carrier and a compound of Formula (I) or Formula (II).
In the present invention it has been discovered that the compounds of Formulae I-IV above are useful as inhibitors of cell-matrix and cell-cell adhesion processes. The present invention includes novel compounds of Formulae I-IV and methods for using such compounds for the prevention or treatment of diseases resulting from abnormal cell adhesion to the extracellular matrix which comprises administering to a host in need of such treatment a therapeutically effective amount of such compound of Formulae I-IV.
In the present invention it has also been discovered that the compounds of Formulae I-IV above are useful as inhibitors of xcex1vxcex23. The compounds of the present invention inhibit the binding of vitronectin to xcex1vxcex23 and inhibit cell adhesion.
The present invention also provides pharmaceutical compositions comprising a compound of Formulae I-IV and a pharmaceutically acceptable carrier.
The compounds of Formulae I-IV of the present invention are useful for the treatment (including prevention) of angiogenic disorders. The term xe2x80x9cangiogenic disordersxe2x80x9d as used herein includes conditions involving abnormal neovascularization, such as tumor metastasis and ocular neovascularization, including, for example, diabetic retinopathy, neovascular glaucoma, age-related macular degeneration, and retinal vein occlusion, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formulae I-IV described above.
The compounds of Formulae I-IV of the present invention may be useful for the treatment or prevention of other diseases which involve cell adhesion processes, including, but not limited to, inflammation, bone degradation, thromboembolic disorders, restenosis, rheumatoid arthritis, asthma, allergies, adult respiratory distress syndrome, graft versus host disease, organ transplantation rejection, septic shock, psoriasis, eczema, contact dermatitis, osteoporosis, osteoarthritis, atherosclerosis, inflammatory bowel disease and other autoimmune diseases. The compounds of Formulae IV of the present invention may also be useful for wound healing.
The term xe2x80x9cthromboembolic disordersxe2x80x9d as used herein includes conditions involving platelet activation and aggregation, such as arterial or venous cardiovascular or cerebrovascular thromboembolic disorders, including, for example, thrombosis, unstable angina, first or recurrent myocardial infarction, ischemic sudden death, transient ischemic attack, stroke, atherosclerosis, venous thrombosis, deep vein thrombosis, thrombophlebitis, arterial embolism, coronary and cerebral arterial thrombosis, myocardial infarction, cerebral embolism, kidney embolisms, pulmonary embolisms, or such disorders associated with diabetes, comprising administering to a mammal in need of such treatment a therapeutically effective amount of a compound of Formulae I-IV described above.
The compounds of the present invention may be used for other ex vivo applications to prevent cellular adhesion in biological samples.
The compounds of the present invention can also be administered in combination with one or more additional therapeutic agents selected from: anti-coagulant or coagulation inhibitory agents, such as heparin or warfarin; anti-platelet or platelet inhibitory agents, such as aspirin, piroxicam, ticlopidine, or clopidogrel; factor Xa inhibitors; thrombin inhibitors such as boropeptides, hirudin or argatroban; or thrombolytic or fibrinolytic agents, such as plasminogen activators, anistreplase, urokinase, or streptokinase.
The compounds of Formulae I-IV of the present invention can be administered in combination with one or more of the foregoing additional therapeutic agents, thereby to reduce the doses of each drug required to achieve the desired therapeutic effect. Thus, the combination treatment of the present invention permits the use of lower doses of each component, with reduced adverse, toxic effects of each component. A lower dosage minimizes the potential of side effects of the compounds, thereby providing an increased margin of safety relative to the margin of safety for each component when used as a single agent. Such combination therapies may be employed to achieve synergistic or additive therapeutic effects for the treatment of thromboembolic disorders.
By xe2x80x9ctherapeutically effective amountxe2x80x9d it is meant an amount of a compound of Formulae I-IV that when administered alone or in combination with an additional therapeutic agent to a cell or mammal is effective to prevent or ameliorate the thromboembolic disease condition or the progression of the disease.
By xe2x80x9cadministered in combinationxe2x80x9d or xe2x80x9ccombination therapyxe2x80x9d it is meant that the compound of Formulae I-IV and one or more additional therapeutic agents are administered concurrently to the mammal being treated. When administered in combination each component may be administered at the same time or sequentially in any order at different points in time. Thus, each component may be administered separately but sufficiently closely in time so as to provide the desired therapeutic effect. The term anti-coagulant agents (or coagulation inhibitory agents), as used herein, denotes agents that inhibit blood coagulation. Such agents include warfarin (available as COUMADIN(trademark)) and heparin.
The term anti-platelet agents (or platelet inhibitory agents), as used herein, denotes agents that inhibit platelet function such as by inhibiting the aggregation, adhesion or granular secretion of platelets. Such agents include the various known non-steroidal anti-inflammatory drugs (NSAIDS) such as aspirin, ibuprofen, naproxen, sulindac, indomethacin, mefenamate, droxicam, diclofenac, sulfinpyrazone, and piroxicam, including pharmaceutically acceptable salts or prodrugs thereof. Of the NSAIDS, aspirin (acetylsalicyclic acid or ASA), and piroxicam. Piroxicam is commercially available from Pfizer, Inc. (New York, N.Y.), as Feldane(copyright). Other suitable anti-platelet agents include ticlopidine and clopidogrel, including pharmaceutically acceptable salts or prodrugs thereof. Ticlopidine and clopidogrel are also preferred compounds since they are known to be gentle on the gastro-intestinal tract in use. Still other suitable platelet inhibitory agents include thromboxane-A2-receptor antagonists and thromboxane-A2-synthetase inhibitors, as well as pharmaceutically acceptable salts or prodrugs thereof.
The phrase thrombin inhibitors (or anti-thrombin agents), as used herein, denotes inhibitors of the serine protease thrombin. By inhibiting thrombin, various thrombin-mediated processes, such as thrombin-mediated platelet activation (that is, for example, the aggregation of platelets, and/or the granular secretion of plasminogen activator inhibitor-1 and/or serotonin) and/or fibrin formation are disrupted. Such inhibitors include boroarginine derivatives and boropeptides, hirudin and argatroban, including pharmaceutically acceptable salts and prodrugs thereof. Boroarginine derivatives and boropeptides include N-acetyl and peptide derivatives of boronic acid, such as C-terminal xcex1-aminoboronic acid derivatives of lysine, ornithine, arginine, homoarginine and corresponding isothiouronium analogs thereof. The term hirudin, as used herein, includes suitable derivatives or analogs of hirudin, referred to herein as hirulogs, such as disulfatohirudin. Boropeptide thrombin inhibitors include compounds described in Kettner et al., U.S. Pat. No. 5,187,157 and European Patent Application Publication Number 293 881 A2, the disclosures of which are hereby incorporated herein by reference. Other suitable boroarginine derivatives and boropeptide thrombin inhibitors include those disclosed in PCT Application Publication Number 92/07869 and European Patent Application Publication Number 471 651 A2, the disclosures of which are hereby incorporated herein by reference, in their entirety.
The phrase thrombolytics (or fibrinolytic) agents (or thrombolytics or fibrinolytics), as used herein, denotes agents that lyse blood clots (thrombi). Such agents include tissue plasminogen activator, anistreplase, urokinase or streptokinase, including pharmaceutically acceptable salts or prodrugs thereof. Tissue plasminogen activator (tPA) is commercially available from Genentech Inc., South San Francisco, Calif. The term anistreplase, as used herein, refers to anisoylated plasminogen streptokinase activator complex, as described, for example, in European Patent Application No. 028,489, the disclosures of which are hereby incorporated herein by reference herein, in their entirety. Anistreplase is commercially available as Eminase(copyright). The term urokinase, as used herein, is intended to denote both dual and single chain urokinase, the latter also being referred to herein as pro-urokinase.
Administration of the compounds of Formulae I-IV of the invention in combination with such additional therapeutic agent, may afford an efficacy advantage over the compounds and agents alone, and may do so while permitting the use of lower doses of each. A lower dosage minimizes the potential of side effects, thereby providing an increased margin of safety.
The compounds of the present invention are also useful as standard or reference compounds, for example as a quality standard or control, in tests or assays involving the binding of vitronectin or fibrinogen to xcex1vxcex23. Such compounds may be provided in a commercial kit, for example, for use in pharmaceutical research involving xcex1vxcex23. The compounds of the present invention may also be used in diagnostic assays involving xcex1vxcex23.
The compounds herein described may have asymmetric centers. Unless otherwise indicated, all chiral, diastereomeric and racemic forms are included in the present invention. Many geometric isomers of olefins, Cxe2x95x90N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. It will be appreciated that compounds of the present invention that contain asymmetrically substituted carbon atoms may be isolated in optically active or racemic forms. It is well known in the art how to prepare optically active forms, such as by resolution of racemic forms or by synthesis, from optically active starting materials. All chiral, diastereomeric, racemic forms and all geometric isomeric forms of a structure are intended, unless the specific stereochemistry or isomer form is specifically indicated.
When any variable (for example but not limited to, R2, R4, R6, R7,R8, R12,and R14, n, etc.) occurs more than one time in any constituent or in any formula, its definition on each occurrence is independent of its definition at every other occurrence. Thus, for example, if a group is shown to be substituted with 0-2 R4, then said group may optionally be substituted with up to two R4 and R4 at each occurrence is selected independently from the defined list of possible R4. Also, by way of example, for the group xe2x80x94N(R5a)2, each of the two R5a substituents on N is independently selected from the defined list of possible R5a. Similarly, by way of example, for the group xe2x80x94C(R7)2xe2x80x94, each of the two R7 substituents on C is independently selected from the defined list of possible R7.
When a bond to a substituent is shown to cross the bond connecting two atoms in a ring, then such substituent may be bonded to any atom on the ring. When a bond joining a substituent to another group is not specifically shown or the atom in such other group to which the bond joins is not specifically shown, then such substituent may form a bond with any atom on such other group.
When a substituent is listed without indicating the atom via which such substituent is bonded to the rest of the compound of Formulae I-IV, then such substituent may be bonded via any atom in such substituent. For example, when the substituent is piperazinyl, piperidinyl, or tetrazolyl, unless specified otherwise, said piperazinyl, piperidinyl, tetrazolyl group may be bonded to the rest of the compound of Formulae I-IV via any atom in such piperazinyl, piperidinyl, tetrazolyl group.
Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By stable compound or stable structure it is meant herein a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term xe2x80x9csubstitutedxe2x80x9d, as used herein, means that any one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom""s normal valency is not exceeded, and that the substitution results in a stable compound. When a substituent is keto (i.e., xe2x95x90O), then 2 hydrogens on the atom are replaced.
As used herein, xe2x80x9calkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms (for example, xe2x80x9cC1-C10xe2x80x9d denotes alkyl having 1 to 10 carbon atoms); xe2x80x9chaloalkylxe2x80x9d is intended to include both branched and straight-chain saturated aliphatic hydrocarbon groups having the specified number of carbon atoms, substituted with 1 or more halogen (for example xe2x80x94CvFw where v=1 to 3 and w=1 to (2v+1)); xe2x80x9calkoxyxe2x80x9d represents an alkyl group of indicated number of carbon atoms attached through an oxygen bridge; xe2x80x9ccycloalkylxe2x80x9d is intended to include saturated ring groups, including mono-, bi-, or polycyclic ring systems, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, and adamantyl; and xe2x80x9cbiycloalkylxe2x80x9d, is intended to include saturated bicyclic ring groups such as [3.3.0]bicyclooctane, [4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin), [2.2.2]bicyclooctane, and so forth. xe2x80x9cAlkenylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more unsaturated carbon-carbon bonds which may occur in any stable point along the chain, such as ethenyl, propenyl and the like; and xe2x80x9calkynylxe2x80x9d is intended to include hydrocarbon chains of either a straight or branched configuration and one or more triple carbon-carbon bonds which may occur in any stable point along the chain, such as ethynyl, propynyl and the like.
The terms xe2x80x9calkylenexe2x80x9d, xe2x80x9calkenylenexe2x80x9d, xe2x80x9cphenylenexe2x80x9d, and the like, refer to alkyl, alkenyl, and phenyl groups, respectively, which are connected by two bonds to the rest of the structure of Formulae I-IV. Such xe2x80x9calkylenexe2x80x9d, xe2x80x9calkenylenexe2x80x9d, xe2x80x9cphenylenexe2x80x9d, and the like, may alternatively and equivalently be denoted herein as xe2x80x9c-(alkyl)-xe2x80x9d, xe2x80x9c-(alkenyl)-xe2x80x9d and xe2x80x9c-(phenyl)-xe2x80x9d, and the like.
xe2x80x9cHaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d as used herein refers to fluoro, chloro, bromo and iodo; and xe2x80x9ccounterionxe2x80x9d is used to represent a small, negatively charged species such as chloride, bromide, hydroxide, acetate, sulfate and the like.
As used herein, xe2x80x9carylxe2x80x9d or xe2x80x9caromatic residuexe2x80x9d is intended to mean phenyl or naphthyl optionally substituted with 1-3 R19; the term xe2x80x9carylalkylxe2x80x9d represents an aryl group attached through an alkyl bridge.
As used herein, xe2x80x9ccarbocyclexe2x80x9d or xe2x80x9ccarbocyclic residuexe2x80x9d is intended to mean any stable 3- to 7-membered monocyclic or bicyclic or 7- to 14-membered bicyclic or tricyclic or an up to 26-membered polycyclic carbon ring, any of which may be saturated, partially unsaturated, or aromatic. Examples of such carbocyles include, but are not limited to, cyclopropyl, cyclopentyl, cyclohexyl, phenyl, biphenyl, naphthyl, indanyl, adamantyl, or tetrahydronaphthyl (tetralin).
As used herein, the term xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocyclicxe2x80x9d is intended to mean a stable 5- to 7-membered monocyclic or bicyclic or 7- to 10-membered bicyclic heterocyclic ring which may be saturated, partially unsaturated, or aromatic, and which consists of carbon atoms and from 1 to 4 heteroatoms independently selected from the group consisting of N, O and S and wherein the nitrogen and sulfur heteroatoms may optionally be oxidized, and the nitrogen may optionally be quaternized, and including any bicyclic group in which any of the above-defined heterocyclic rings is fused to a benzene ring. The heterocyclic ring may be attached to its pendant group at any heteroatom or carbon atom which results in a stable structure. The heterocyclic rings described herein may be substituted on carbon or on a nitrogen atom if the resulting compound is stable. Examples of such heterocycles include, but are not limited to, pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, tetrazolyl, benzofuranyl, benzothiophenyl, indolyl, indolenyl, isoxazolinyl, isoxazolyl, quinolinyl, isoquinolinyl, benzimidazolyl, piperidinyl, 4-piperidonyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl or octahydroisoquinolinyl, azocinyl, triazinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, thianthrenyl, pyranyl, isobenzofuranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, pyrrolyl, imidazolyl, pyrazolyl, isothiazolyl, isoxazolinyl, isoxazolyl, oxazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, 1H-indazolyl, purinyl, 4H-quinolizinyl, isoquinolinyl, quinolinyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazole, carbazole, xcex2-carbolinyl, phenanthridinyl, acridinyl, perimidinyl, phenanthrolinyl, phenazinyl, phenarsazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, pyrrolidinyl, pyrrolinyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperidinyl, piperazinyl, indolinyl, isoindolinyl, quinuclidinyl, morpholinyl or oxazolidinyl. Also included are fused ring and spiro compounds containing, for example, the above heterocycles.
At used herein, the term xe2x80x9cheteroarylxe2x80x9d refers to aromatic heterocyclic groups. Such heteroaryl groups are preferably 5-6 membered monocylic groups or 8-10 membered fused bicyclic groups. Examples of such heteroaryl groups include, but are not limited to pyridyl (pyridinyl), pyrimidinyl, furanyl (furyl), thiazolyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, indolyl, isoxazolyl, oxazolyl, pyrazinyl, pyrimidinyl, pyridazinyl, benzofuranyl, benzothienyl, benzimidazolyl, quinolinyl, or isoquinolinyl.
As used herein, xe2x80x9cpharmaceutically acceptable saltsxe2x80x9d refer to derivatives of the disclosed compounds wherein the parent compound of Formulae I-IV is modified by making acid or base salts of the compound of Formulae I-IV. Examples of pharmaceutically acceptable salts include, but are not limited to, mineral or organic acid salts of basic residues such as amines; alkali or organic salts of acidic residues such as carboxylic acids; and the like.
xe2x80x9cProdrugsxe2x80x9d are considered to be any covalently bonded carriers which release the active parent drug according to Formulae I-IV in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of Formulae I-IV are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds of Formulae I-IV wherein hydroxyl, amino, sulfhydryl, or carboxyl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, sulfhydryl, or carboxyl group respectively. Examples of prodrugs include, but are not limited to, acetate, formate and benzoate derivatives of alcohol and amine functional groups in the compounds of Formulae I-IV, and the like. Examples of representative carboxyl and amino prodrugs are included under the definition of R2, R3, and Y.
The pharmaceutically acceptable salts of the compounds of Formulae I-IV include the conventional non-toxic salts or the quaternary ammonium salts of the compounds of Formulae I-IV formed, for example, from non-toxic inorganic or organic acids. For example, such conventional non-toxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic, and the like.
The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of Formulae I-IV which contain a basic or acidic moiety by conventional chemical methods. Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.
The pharmaceutically acceptable salts of the acids of Formulae I-IV with an appropriate amount of a base, such as an alkali or alkaline earth metal hydroxide e.g. sodium, potassium, lithium, calcium, or magnesium, or an organic base such as an amine, e.g., dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine and the like, or a quaternary ammonium hydroxide such as tetramethylammoinum hydroxide and the like.
As discussed above, pharmaceutically acceptable salts of the compounds of the invention can be prepared by reacting the free acid or base forms of these compounds with a stoichiometric amount of the appropriate base or acid, respectively, in water or in an organic solvent, or in a mixture of the two; generally, nonaqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile are preferred. Lists of suitable salts are found in Remington""s Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa., 1985, p. 1418, the disclosure of which is hereby incorporated by reference.
The disclosures of all of the references cited herein are hereby incorporated herein by reference in their entirety.
The compounds of the present invention can be prepared in a number of ways well known to one skilled in the art of organic synthesis. The compounds of the present invention can be synthesized using the methods described below, together with synthetic methods known in the art of synthetic organic chemistry, or variations thereof as appreciated by those skilled in the art. Preferred methods include, but are not limited to, those described below. All literature cited herein is incorporated in its entirety by reference.
Compounds of Formulae I-IV can be conveniently prepared by cyclization of aniline derived aminomethylenemalonates (Gould-Jacobs reaction, for a review of quinolone synthesis, see Radl, S.; Bouzard, D. Recent Advances in the Synthesis of Antibacterial Quinolones. Heterocycles 1992, 34:2143-2177).
Scheme I illustrates a synthetic sequence which will provide the quinolones of this invention. Reaction of a 3-Bromoaniline with diethyl ethoxymethylenemalonate (Albrect, R. Prog. Drug Res. 1977, 21:9) results in a vinylogous amide which is cyclized in diphenyl ether at reflux to afford the 7-bromoquinolone. After N1-alkylation, the bromide is converted to an olefin via Stille coupling to a vinyltin species or Heck olefination using styrene. Ozonolysis of the olefin provides the aldehyde.
Reductive amination of the intermediate aldehyde (for suitable methods see, Abdel-Magid, A. F.; Maryanoff, C. A.; Carson, K. G. Tetrahedron Lett. 1990, 31:5595-5598, and references contained therein ) with a variety of heteroaryl amines, which may additionally contain suitable protecting groups, provides the substituted amines. Alternatively, depending on the nature of the heterocyclic amine, the reductive amination can be carried out in a two step procedure, wherein initial formation of an imine is carried out by treatment of the aldehyde with the desired amine in the presence of a dehydrating agent such as magnesium sulfate, sodium sulfate, or molecular sieves, in a suitable solvent such as carbon tetrachloride, methylene chloride, benzene or toluene (for example see, Modern Synthetic Reactions 2nd ed. House, H. O., Benjamin/Cummings Publishing Co., Menlo Park, Calif., 1972.). The imine is subsequently reduced using one of a variety of reducing agents such as sodium borohydride, sodium cyanoborohydride, or sodium triacetoxyborohydride, in a suitable solvent such as methanol, ethanol, tetrahydrofuran, dioxane or 1,2-dichloroethane, to provide the desired amine. Subsequent saponification of the ester using conventional methods known to one skilled in the art of organic synthesis gives the desired acids. In the case of tert-butyl esters the acid may be produced either by the action of trifluoroacetic acid with or without an inert solvent such as methylene chloride, or by the action of anhydrous HCl in a solvent such as ether or dioxane. Coupling of the resulting acids to appropriately substituted xcex1- or xcex2-amino esters affords an intermediate which can be deprotected to give compounds of Formulae I-IV. The coupling is carried out using any of the many methods for the formation of amide bonds known to one skilled in the art of organic synthesis. These methods include but are not limited to conversion of the acid to the corresponding acid chloride, or use of standard coupling procedures such as the azide method, mixed carbonic acid anhydride (isobutyl chloroformate) method, carbodiimide (dicyclohexylcarbodiimide, diisopropylcarbodiimide, or water-soluble carbodiimides) method, active ester (p-nitrophenyl ester, N-hydroxysuccinic imido ester) method, carbonyldiimidazole method, phosphorus reagents such as BOP-Cl. Some of these methods (especially the carbodiimide) can be enhanced by the addition of 1-hydroxybenzotriazole. Global deprotection of the remaining protecting groups may be accomplished by methods known to one skilled in the art (for example see, Protective Groups in Organic Synthesis 2nd,ed. Greene, T. W., and Wuts, P. G. M., John Wiley and Sons, Inc. New York, 1991.). 
The compounds of the present invention wherein Y is an oxyalkoxy group, e.g. alkoxycarbonyloxyalkoxy, may be prepared by reacting a suitably protected carboxylic acid of Formulae I-IV with an e.g. an alkoxycarbonyloxyalkyl chloride in the presence of an iodide source, such as tetrabutylammonium iodide or potassium iodide, and an acid scavenger, such as triethylamine or potassium carbonate, using procedures known to those skilled in the art.
As an alternative to the quinolone synthesis outlined above, the quinolone nucleus may be formed using the route illustrated in Scheme II. Similar methodology for the preparation of quinolones was first described in German patent application DE3142854. Starting from a 4-bromo-3-fluoro-benzoyl chloride, condensation with malonic acid monoethyl ester monopotassium salt gives a benzoyl acetate that is subsequently reacted with triethyl orthoformate. The resulting ethoxymethylene derivative is reacted with a primary amine and cyclized to the quinolone. 
The appropriately substituted racemic xcex2-amino acids may be purchased commercially or, as is shown in Scheme III, Method 1, prepared from the appropriate aldehyde, malonic acid and ammonium acetate according to the procedure of Johnson and Livak, J. Am. Chem. Soc. 1936, 58, 299. Racemic xcex2-substituted-xcex2-amino esters may be prepared through the reaction of dialkylcuprates or alkyllithiums with 4-benzoyloxy-2-azetidinone followed by treatment with anhydrous ethanol (Scheme III, Method 2) or by reductive amination of xcex2-keto esters as is described in published PCT patent application WO9316038 (see also Rico et al., J. Org. Chem. 1993, 58, 7948-51). Enantiomerically pure xcex2-substituted-xcex2-amino acids can be obtained through the optical resolution of the racemic mixture or can be prepared using numerous methods, including: Arndt-Eistert homologation of the corresponding a-amino acids as shown in Scheme III, Method 3 (see Meier, and Zeller, Angew. Chem. Int. Ed. Engl. 1975, 14, 32; Rodriguez, et al. Tetrahedron Lett. 1990, 31, 5153; Greenlee, J. Med. Chem. 1985, 28, 434 and references cited within); and through an enantioselective hydrogenation of a dehydroamino acid as is shown in Scheme III, Method 4 (see Asymmetric Synthesis, Vol. 5, (Morrison, ed.) Academic Press, New York, 1985). A comprehensive treatise on the preparation of xcex2-amino acid derivatives may be found in published PCT patent application WO 9307867, the disclosure of which is hereby incorporated by reference. 
The synthesis of N2-substituted diaminopropionic acid derivatives can be carried out via Hoffman rearrangement of a wide variety of asparagine derivatives as described in Waki, M., et al., Synthesis, 266-268, (1981).
A convenient preparation of suitably protected 2-aminoimidazoles is outlined in Scheme IV. 
Additional compounds of Formulae I-IV where R9 is N(R16)R17 can be prepared from the compounds of Scheme I, wherein R16 is Cbz (benzyloxycarbonyl),is shown in Scheme V. Selective removal of the Cbz group may be accomplished by hydrogenation using palladium on carbon in a suitable solvent such as methanol or ethanol.
The resulting amines can be converted to additional compound of Formulae I-IV by treatment with a wide variety of reagents, for example, acyl halides, chloroformates, isocyanates, sulfonylchlorides, chlorosulfonamides, and sulfonylisocyanates, etc. using standard methods. 
Scheme VI illustrates a synthetic sequence which will provide the naphthyridines of this invention. Reaction of 2,4-dichloronicotinic acid with phosphorus pentachloride provides the acid chloride which reacts with ethyl malonate giving nicotinyl acetate. Reaction of nicotinyl acetate with ethyl orthoformate provides ethoxyethylene malonate, which then reacts with the desired amine, resulting in intermediate which can be cyclized in the presence of a base such as sodium hydride or potassium carbonate to yield the desired 6-chloronaphthyridine. (J. Med. Chem. 1992, 35, 518-525). Coupling of the desired 6-chloronaphthyridine with tributylvinyltin provides an olefin, 6-vinylnaphthyridine, (J. Heterocyclic chem. 1991, 28, 191) upon which further synthetic transformation as in Scheme I affords the naphthyridines of this invention. 
The detailed processes for preparing the compounds of Formulae I-IV are illustrated by the following Examples. It is, however, understood that this invention is not limited to the specific details of these examples. Proton nuclear magnetic resonance spectra (1H NMR) were measured in chloroform-d (CDCl3) unless otherwise specified, and reported in parts per million (ppm) downfield from tetramethylsilane (TMS). The coupling patterns are reported as follows: s, singlet; d, doublet; t, triplet; q, quartet; qt, quintet; m, multiplet.